Faculty Profiles - SAHARA Naruhiko

写真a

SAHARA Naruhiko

Organization

Brain Research Institute Center for Integrated Human Brain Science Specially Appointed Associate Professor

Homepage

https://kaken.nii.ac.jp/d/r/40261185.ja.html

External link

Degree

PhD ( 1998.3 Tokyo University of Science )

Research Interests

タウオパチー
プレセニリン
カスパーゼ
老化
神経変性
老人斑
神経原線維
アミロイドβペプチド
APP
神経毒性
JNK
tau
mouse model
アポトーシス
神経原線維変化
タウ
家族性アルツハイマー病
包括脳ネットワーク
アルツハイマー病
神経細胞死
FTDP-17
蛋白質凝集中間体

Research Areas

Life Science / Anatomy and histopathology of nervous system
Life Science / Pathophysiologic neuroscience
Life Science / Neuroscience-general

Research History (researchmap)

Niigata University Brain Research Institute Center for Integrated Human Brain Science Department of Functional Neurology and Neurosurgery Associate Professor

2025.4

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Country：Japan

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National Institutes for Quantum and Radiological Science and Technology

2021.7 - 2025.3

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National Institutes for Quantum Science and Technology

2019.4 - 2025.3

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放射線医学総合研究所脳機能イメージング研究部チームリーダー

2017.7 - 2019.3

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放射線医学総合研究所脳機能イメージング研究部サブリーダー

2016.4 - 2017.6

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放射線医学総合研究所分子イメージング研究センターサブリーダー

2015.4 - 2016.3

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放射線医学総合研究所分子イメージング研究センター主任研究員

2013.7 - 2015.3

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University of Florida Department of Neuroscience Assistant Professor

2010.7 - 2013.7

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Mayo Clinic Laboratory of Neurodegenerative Disease Modeling Associate Consultant & Assistant Professor

2009.3 - 2010.7

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Mayo Clinic Laboratory of Neurodegenerative Disease Modeling Senior Research Associate

2008.10 - 2009.3

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理化学研究所脳科学総合研究センターアルツハイマー病研究チーム副チームリーダー

2006.4 - 2008.10

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理化学研究所脳科学総合研究センターアルツハイマー病研究チーム研究員

2003.4 - 2006.3

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Mayo Clinic Laboratory of Neurochemistry Research Fellow

2000.4 - 2003.3

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Osaka City University Medical School Research Assistant

1998.7 - 2000.3

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東京都精神医学総合研究所分子生物学研究室技術員

1992.4 - 1998.6

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Research History

Niigata University Center for Integrated Human Brain Science, Brain Research Institute Specially Appointed Associate Professor

2025.4

Education

Tokyo University of Science Graduate School of Science and Technology 応用生物科学専攻博士後期課程

1990.4 - 1992.3

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Country： Japan

Notes： 1998年3月、理学博士

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Tokyo University of Science Graduate School of Science and Technology 応用生物科学専攻修士課程

1988.4 - 1990.3

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Country： Japan

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Tokyo University of Science 理工学部応用生物科学科

1984.4 - 1988.3

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Country： Japan

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Papers

Diverse tau pathologies in late-life mood disorders revealed by PET and autopsy assays. International journal

Shin Kurose, Sho Moriguchi, Manabu Kubota, Kenji Tagai, Yuki Momota, Masanori Ichihashi, Yasunori Sano, Hironobu Endo, Kosei Hirata, Yuko Kataoka, Ryoji Goto, Yuki Mashima, Yasuharu Yamamoto, Hisaomi Suzuki, Shinichiro Nakajima, Masashi Mizutani, Terunori Sano, Kazunori Kawamura, Ming-Rong Zhang, Harutsugu Tatebe, Takahiko Tokuda, Mitsumoto Onaya, Masaru Mimura, Naruhiko Sahara, Hidehiko Takahashi, Hiroyuki Uchida, Masaki Takao, Jeffrey H Meyer, Makoto Higuchi, Keisuke Takahata

Alzheimer's & dementia : the journal of the Alzheimer's Association 21 ( 6 ) e70195 2025.6

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Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Late-life mood disorders (LLMDs) may represent prodromal manifestations of neurodegenerative dementia; however, the neuropathological basis of LLMDs, including depression and bipolar disorder, remains unclear. We aimed to investigate the involvement of Alzheimer's disease (AD) and non-AD tau pathologies in LLMD participants. METHODS: Fifty-two LLMD participants and 47 age- and sex-matched healthy controls (HCs) underwent tau and amyloid beta (Aβ) positron emission tomography (PET) imaging using 18F-florzolotau and 11C-Pittsburgh compound B. Additionally, we conducted a clinicopathological correlation analysis in 208 autopsy cases, including various neurodegenerative diseases. RESULTS: LLMD participants were more likely to be tau PET and Aβ PET positive than HCs. The PET results were supported by the post mortem results that showed a higher likelihood of diverse tauopathies in patients with late-life mania or depression than those without. DISCUSSION: Our PET and autopsy assays suggest that AD and diverse non-AD tau pathologies might underlie the neuropathological basis of some LLMD cases. HIGHLIGHTS: Late-life mood disorders (LLMDs) may represent prodromal states of dementia. The neuropathological basis of LLMDs remains unclear. LLMD subjects were highly likely to be tau positron emission tomography (PET) positive. Brain bank data supported our PET results. Alzheimer's disease (AD) and diverse non-AD tau pathologies can contribute to LLMDs.

DOI： 10.1002/alz.70195

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Neuronal deterioration associated with hyperexcitability under mild chronic cerebral hypoperfusion. International journal

Takuya Urushihata, Manami Takahashi, Masafumi Shimojo, Yuhei Takado, Nobuhiro Nitta, Yosuke Tajima, Kazuto Masamoto, Iwao Kanno, Yutaka Tomita, Naruhiko Sahara, Masaya Takahashi, Takayuki Obata, Hiroshi Ito, Tetsuro Yamashita, Tetsuya Suhara, Makoto Higuchi, Hiroyuki Takuwa

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 271678X251328971 2025.5

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Chronic cerebral hypoperfusion (CCH) has been indicated to impair cognitive and diverse brain functions. However, the neural mechanisms linking these cerebrovascular and phenotypic alterations remain unclear. Here, we investigated the effect of CCH on neuronal activity in male mice with unilateral common carotid artery occlusion using optical imaging and MRI. Our examinations revealed enhanced neuronal activity in concurrence with increased glutamate and tissue acidosis up to seven days after occlusion. At 21-28 days after occlusion, neuronal activity decreased below baseline, while the acidotic but not the hyperglutamatergic state persisted. Notably, pharmacological blockade of the N-methyl-D-aspartate-type glutamate receptor, initiated at an early stage of CCH, suppressed the onset of neuronal hyperexcitation and subsequent deficits in neuronal activity. Altogether, we provide experimental evidence that CCH induces a glutamate surge and results in neuronal hyperexcitation at an early phase, which thereafter gives rise to a non-lethal but progressive deterioration of neuronal functions.

DOI： 10.1177/0271678X251328971

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iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau. International journal

Keiko Imamura, Ayako Nagahashi, Aya Okusa, Tomoki Sakasai, Kayoko Tsukita, Yumiko Kutoku, Yutaka Ohsawa, Yoshihide Sunada, Naruhiko Sahara, Nicholas M Kanaan, Makoto Higuchi, Kohji Mori, Manabu Ikeda, Haruhisa Inoue

European journal of cell biology 104 ( 2 ) 151484 - 151484 2025.3

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Language：English Publishing type：Research paper (scientific journal)

Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disorder that affects the frontal and temporal lobes, which are crucial for regulating personality, behavior, and language. Pathologically, FTLD is characterized by Tau protein accumulation and neuronal death. In our effort to identify disease-modifying treatments, we conducted drug screening using neurons derived from induced pluripotent stem cells (iPSCs) of FTLD-Tau patients. This screening identified gabapentin as an existing drug that suppresses neuronal cell death with suppressed accumulation of Tau oligomers. Treatment with gabapentinoids, including pregabalin and mirogabalin, demonstrated similar neuroprotective effects. These compounds bind to the α2δ subunit of voltage-dependent calcium channels and specifically target the two isoforms α2δ-1 and α2δ-2. To determine which isoform is involved in the neurodegeneration seen in FTLD-Tau, we employed a knockout approach using iPSCs, which revealed that α2δ-2, encoded by CACNA2D2, plays a key role in the degeneration of FTLD-Tau neurons. Moreover, Neural organoids of FTLD-Tau exhibited features indicative of neurodegeneration, and CACNA2D2 knockout reversed a part of the gene expression alterations associated with these neurodegenerative features. These findings suggest that α2δ-2 may be a promising target for disease-modifying therapies in FTLD-Tau.

DOI： 10.1016/j.ejcb.2025.151484

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Distinct tau pathologies in the nucleus basalis of Meynert between early-onset and late-onset Alzheimer's disease patients revealed by positron emission tomography. International journal

Hisaomi Suzuki, Kenji Tagai, Maiko Ono, Hiroshi Shimizu, Hironobu Endo, Hideki Matsumoto, Manabu Kubota, Yuko Kataoka, Sho Moriguchi, Shin Kurose, Masanori Ichihashi, Hitoshi Shinotoh, Kiwamu Matsuoka, Naomi Kokubo, Harutsugu Tatebe, Sayo Matsuura, Yasuharu Yamamoto, Yuki Momota, Kazunori Kawamura, Ming-Rong Zhang, Yuhei Takado, Hitoshi Shimada, Takahiko Tokuda, Mitsumoto Onaya, Masaru Mimura, Akiyoshi Kakita, Naruhiko Sahara, Hiroyuki Uchida, Makoto Higuchi, Keisuke Takahata

Journal of Alzheimer's disease : JAD 102 ( 4 ) 1271 - 1285 2024.12

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BACKGROUND: Tau accumulation in the nucleus basalis of Meynert (nbM) has been documented in Alzheimer's disease (AD), but its relationship to neuropathological changes in other brain regions and cognitive deficits remains unclear, particularly between early-onset AD (EOAD) and late-onset AD (LOAD). OBJECTIVE: To evaluate tau accumulation patterns in the nbM and other brain regions in EOAD and LOAD using 18F-florzolotau PET and examine correlations with cognitive function. METHODS: Thirty-eight amyloid-positive AD patients (15 EOAD, 23 LOAD) and 46 healthy controls underwent 18F-florzolotau PET. Tau levels were quantified in the nbM and Braak-staging regions. Postmortem brain samples were examined to assess 18F-florzolotau binding to tau deposits. RESULTS: EOAD showed a higher overall tau burden, including in the nbM, compared with LOAD. However, nbM tau levels correlated more strongly with cognitive decline in LOAD than EOAD. The relationship between nbM tau and neocortical tau differed between EOAD and LOAD. Histopathology revealed abundant 18F-florzolotau labeling of neurofibrillary tangles (NFTs) and ghost tangles in AD nbM samples. CONCLUSIONS: This study provides the first in vivo PET evidence of differential nbM tau pathology between EOAD and LOAD, with higher accumulation but weaker correlation to cognition in EOAD. The distinct relationships between nbM and cortical tau in EOAD and LOAD suggest divergent pathological trajectories. 18F-florzolotau PET successfully visualized NFTs and extracellular ghost tangles in the nbM across AD stages. These findings highlight the importance of considering age of onset when evaluating tau pathology and its clinical correlates in AD.

DOI： 10.1177/13872877241297382

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SingleMAPTknock-in mouse models of frontotemporal dementia for sharing with the neurodegenerative research community

Takahiro Morito, Mohan Qi, Naoko Kamano, Hiroki Sasaguri, Sumi Bez, Martha Foiani, Keren Duff, Seico Benner, Toshihiro Endo, Hiroshi Hama, Hiroshi Kurokawa, Atushi Miyawaki, Hiroshi Mizuma, Naruhiko Sahara, Masafumi Shimojo, Makoto Higuchi, Takaomi C. Saido, Naoto Watamura

2024.11

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Publisher：Cold Spring Harbor Laboratory

Abstract

We recently reported development of humanMAPTknock-in mice that carry single or double pathogenic mutations of frontotemporal dementia. However, it takes more than 14 months for the line with the most aggressive phenotypes to exhibit tau pathology without forming high-order tau oligomers, along with concomitant abnormal behavior. We thus generatedMAPTknock-in mice carrying triple mutations, among which theMAPTP301S;Int10+3;S320Fline exhibited robust pathology starting earlier than 6 months. Tau accumulation took place mainly in the thalamus, hypothalamus, amygdala and entorhinal cortex, but less so in the hippocampus, leading to synaptic loss, atrophy and behavioral abnormalities. CrossbreedingMAPTP301S;Int10+3;S320FwithAppknock-in miceAppNL-G-Fresulted in the manifestation of tau pathology in the hippocampus and cortex. These mutant mice will be valuable tools for understanding the mechanisms of frontotemporal dementia, Alzheimer’s disease and other tauopathies.

DOI： 10.1101/2024.11.15.623736

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A novel tauopathy model mimicking molecular and spatial aspects of human tau pathology Reviewed International journal

Rin Yanai, Tomoki T Mitani, Etsuo A Susaki, Takeharu Minamihisamatsu, Masafumi Shimojo, Yuri Saito, Hiroshi Mizuma, Nobuhiro Nitta, Daita Kaneda, Yoshio Hashizume, Gen Matsumoto, Kentaro Tanemura, Ming-Rong Zhang, Makoto Higuchi, Hiroki R Ueda, Naruhiko Sahara

Brain Communications 6 ( 5 ) fcae326 2024.9

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Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

Abstract

Creating a mouse model that recapitulates human tau pathology is essential for developing strategies to intervene in tau-induced neurodegeneration. However, mimicking the pathological features seen in human pathology often involves a trade-off with artificial effects such as unexpected gene insertion and neurotoxicity from the expression system. To overcome these issues, we developed the rTKhomo mouse model by combining a transgenic CaMKII-tTA system with a P301L mutated 1N4R human tau knock-in at the Rosa26 locus with a C57BL/6J background. This model closely mimics human tau pathology, particularly in the hippocampal CA1 region, showing age-dependent tau accumulation, neuronal loss, and neuroinflammation. Notably, whole-brain 3D staining and light-sheet microscopy revealed a spatial gradient of tau deposition from the entorhinal cortex to the hippocampus, similar to the spatial distribution of Braak neurofibrillary tangle (NFT) staging. Furthermore, [18F]PM-PBB3 positron emission tomography (PET) imaging enabled the quantification and live monitoring of tau deposition. The rTKhomo mouse model shows potential as a promising next-generation preclinical tool for exploring the mechanisms of tauopathy and for developing interventions targeting the spatial progression of tau pathology.

DOI： 10.1093/braincomms/fcae326

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descSPIM: an affordable and easy-to-build light-sheet microscope optimized for tissue clearing techniques. International journal

Kohei Otomo, Takaki Omura, Yuki Nozawa, Steven J Edwards, Yukihiko Sato, Yuri Saito, Shigehiro Yagishita, Hitoshi Uchida, Yuki Watakabe, Kiyotada Naitou, Rin Yanai, Naruhiko Sahara, Satoshi Takagi, Ryohei Katayama, Yusuke Iwata, Toshiro Shiokawa, Yoku Hayakawa, Kensuke Otsuka, Haruko Watanabe-Takano, Yuka Haneda, Shigetomo Fukuhara, Miku Fujiwara, Takenobu Nii, Chikara Meno, Naoki Takeshita, Kenta Yashiro, Juan Marcelo Rosales Rocabado, Masaru Kaku, Tatsuya Yamada, Yumiko Oishi, Hiroyuki Koike, Yinglan Cheng, Keisuke Sekine, Jun-Ichiro Koga, Kaori Sugiyama, Kenichi Kimura, Fuyuki Karube, Hyeree Kim, Ichiro Manabe, Tomomi Nemoto, Kazuki Tainaka, Akinobu Hamada, Hjalmar Brismar, Etsuo A Susaki

Nature communications 15 ( 1 ) 4941 - 4941 2024.6

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Despite widespread adoption of tissue clearing techniques in recent years, poor access to suitable light-sheet fluorescence microscopes remains a major obstacle for biomedical end-users. Here, we present descSPIM (desktop-equipped SPIM for cleared specimens), a low-cost ($20,000-50,000), low-expertise (one-day installation by a non-expert), yet practical do-it-yourself light-sheet microscope as a solution for this bottleneck. Even the most fundamental configuration of descSPIM enables multi-color imaging of whole mouse brains and a cancer cell line-derived xenograft tumor mass for the visualization of neurocircuitry, assessment of drug distribution, and pathological examination by false-colored hematoxylin and eosin staining in a three-dimensional manner. Academically open-sourced ( https://github.com/dbsb-juntendo/descSPIM ), descSPIM allows routine three-dimensional imaging of cleared samples in minutes. Thus, the dissemination of descSPIM will accelerate biomedical discoveries driven by tissue clearing technologies.

DOI： 10.1038/s41467-024-49131-1

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Imaging α-synuclein pathologies in animal models and patients with Parkinson's and related diseases. International journal

Hironobu Endo, Maiko Ono, Yuhei Takado, Kiwamu Matsuoka, Manami Takahashi, Kenji Tagai, Yuko Kataoka, Kosei Hirata, Keisuke Takahata, Chie Seki, Naomi Kokubo, Masayuki Fujinaga, Wakana Mori, Yuji Nagai, Koki Mimura, Katsushi Kumata, Tatsuya Kikuchi, Aki Shimozawa, Sushil K Mishra, Yoshiki Yamaguchi, Hiroshi Shimizu, Akiyoshi Kakita, Hiroyuki Takuwa, Hitoshi Shinotoh, Hitoshi Shimada, Yasuyuki Kimura, Masanori Ichise, Tetsuya Suhara, Takafumi Minamimoto, Naruhiko Sahara, Kazunori Kawamura, Ming-Rong Zhang, Masato Hasegawa, Makoto Higuchi

Neuron 112 ( 15 ) 2540 - 2557 2024.5

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Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development.

DOI： 10.1016/j.neuron.2024.05.006

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Clinical and Pathological Features of FTDP-17 with MAPT p.K298_H299insQ Mutation. International journal

Hiroyuki Morino, Takashi Kurashige, Yukiko Matsuda, Maiko Ono, Naruhiko Sahara, Tomohiro Miyasaka, Yoshiyuki Soeda, Hitoshi Shimada, Yu Yamazaki, Tetsuya Takahashi, Yuishin Izumi, Hidefumi Ito, Hirofumi Maruyama, Makoto Higuchi, Koji Arihiro, Tetsuya Suhara, Akihiko Takashima, Hideshi Kawakami

Movement disorders clinical practice 11 ( 6 ) 720 - 727 2024.4

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BACKGROUND: MAPT is a causative gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), a hereditary degenerative disease with various clinical manifestations, including progressive supranuclear palsy, corticobasal syndrome, Parkinson's disease, and frontotemporal dementia. OBJECTIVES: To analyze genetically, biochemically, and pathologically multiple members of two families who exhibited various phenotypes of the disease. METHODS: Genetic analysis included linkage analysis, homozygosity haplotyping, and exome sequencing. We conducted tau protein microtubule polymerization assay, heparin-induced tau aggregation, and western blotting with brain lysate from an autopsy case. We also evaluated abnormal tau aggregation by using anti-tau antibody and PM-PBB3. RESULTS: We identified a variant, c.896_897insACA, p.K298_H299insQ, in the MAPT gene of affected patients. Similar to previous reports, most patients presented with atypical parkinsonism. Biochemical analysis revealed that the mutant tau protein had a reduced ability to polymerize microtubules and formed abnormal fibrous aggregates. Pathological study revealed frontotemporal lobe atrophy, midbrain atrophy, depigmentation of the substantia nigra, and four-repeat tau-positive inclusions in the hippocampus, brainstem, and spinal cord neurons. The inclusion bodies also stained positively with PM-PBB3. CONCLUSIONS: This study confirmed that the insACA mutation caused FTDP-17. The affected patients showed symptoms resembling Parkinson's disease initially and symptoms of progressive supranuclear palsy later. Despite the initial clinical diagnosis of frontotemporal dementia in the autopsy case, the spread of lesions could explain the process of progressive supranuclear palsy. The study of more cases in the future will help clarify the common pathogenesis of MAPT mutations or specific pathogeneses of each mutation.

DOI： 10.1002/mdc3.14042

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Research on the molecular mechanism of singularity phenomenon in neurological disorders

Hiroko Bannai, Akihiko Takashima, Yoshiyuki Soeda, Hideaki Yoshimura, Gen Matsumoto, Naruhiko Sahara, Michio Hiroshima, Mitsuru Hattori, Takeharu Nagai

Biophysics and Physicobiology 21 ( Supplemental ) e211008 2024

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Language：English Publishing type：Research paper (scientific journal) Publisher：Biophysical Society of Japan

DOI： 10.2142/biophysico.bppb-v21.s008

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元プロボクサーにおけるタウ沈着物の分布と伝播(Distribution and propagation of tau deposits in former professional boxers)

高畑圭輔, 互健二, 宮田真里, 建部陽嗣, 久保田学, 黒瀬心, 市橋雅典, 遠藤浩, 木村泰之, 市瀬正則, 北村聡一郎, 片岡優子, 平田浩聖, 篠遠仁, 斎藤文恵, 百田友紀, 徳田隆彦, 三村將, 佐原成彦, 樋口真人

Dementia Japan 37 ( 4 ) 654 - 654 2023.10

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Language：English Publisher：(一社)日本認知症学会

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晩発性双極性障害におけるタウ病態 Florzolotau PETを用いた研究(Tau pathologies in late-onset bipolar disorder: A PET study with florzolotau)

黒瀬心, 高畑圭輔, 互健二, 久保田学, 森口翔, 遠藤浩信, 市橋雅典, 平田浩聖, 片岡優子, 大矢雅樹, 眞島裕樹, 百田友紀, 鈴木寿臣, 関千江, 徳田隆彦, 三村將, 内田裕之, 佐原成彦, 樋口真人

Dementia Japan 37 ( 4 ) 669 - 669 2023.10

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Language：English Publisher：(一社)日本認知症学会

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重篤な脳障害に続発するタウオパチーサリン後遺症とCOVID-19関連脳症

高畑圭輔, 加藤英生, 黒瀬心, 森口翔, 互健二, 宮田真里, 市橋雅典, 遠藤浩信, 建部陽嗣, 佐々木健至, 関千江, 片岡優子, 大矢雅樹, 関守信, 徳田隆彦, 西尾慶之, 八田耕太郎, 三村將, 佐原成彦, 樋口真人

Dementia Japan 37 ( 4 ) 693 - 693 2023.10

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Language：Japanese Publisher：(一社)日本認知症学会

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Diagnostic and therapeutic targeting of pathological tau proteins in neurodegenerative disorders. Reviewed International journal

Naruhiko Sahara, Makoto Higuchi

FEBS open bio 14 ( 2 ) 165 - 180 2023.9

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Language：English Publishing type：Research paper (scientific journal)

Tauopathies, characterized by fibrillar tau accumulation in neurons and glial cells, constitute a major neuropathological category of neurodegenerative diseases. Neurofibrillary tau lesions are strongly associated with cognitive deficits in these diseases, but the causal mechanisms underlying tau-induced neuronal dysfunction remain unresolved. Recent advances in cryo-electron microscopy examination have revealed various core structures of tau filaments from different tauopathy patients, which can be used to classify tauopathies. In vivo visualization of tau pathology is now available using several tau positron emission tomography tracers. Among these radioprobes, PM-PBB3 allows high-contrast imaging of tau deposits in the brains of patients with diverse disorders and tauopathy mouse models. Selective degradation of pathological tau species by the ubiquitin-proteasome system or autophagy machinery is a potential therapeutic strategy. Alternatively, the non-cell-autonomous clearance of pathological tau species through neuron-glia networks could be reinforced as a disease-modifying treatment. In addition, the development of neuroinflammatory biomarkers is required for understanding the contribution of immunocompetent cells in the brain to preventing neurodegeneration. This review provides an overview of the current research and development of diagnostic and therapeutic agents targeting divergent tau pathologies.

DOI： 10.1002/2211-5463.13711

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Selective dysfunction of fast-spiking inhibitory interneurons and disruption of perineuronal nets in a tauopathy mouse model International journal

Takehiro Kudo, Hiroyuki Takuwa, Manami Takahashi, Takuya Urushihata, Masafumi Shimojo, Kazuaki Sampei, Mitsugu Yamanaka, Yutaka Tomita, Naruhiko Sahara, Tetsuya Suhara, Makoto Higuchi

iScience 26 ( 4 ) 106342 - 106342 2023.4

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Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

In Alzheimer's disease (AD), network hyperexcitability is frequently observed and associated with subsequent cognitive impairment. Dysfunction of inhibitory interneurons (INs) is thought to be one of the key biological mechanisms of hyperexcitability. However, it is still unknown how INs are functionally affected in tau pathology, which is a major pathology in AD. To clarify this, we evaluated the neuronal activity of cortical INs in 6-month-old rTg4510 mice, a model of tauopathy. Calcium imaging with mDlx enhancer-driven labeling revealed that neuronal activity in INs was decreased in rTg4510 mice. In the patch clamp recording, the firing properties of fast-spiking INs were altered so as to reduce their activity in rTg4510 mice. In parallel with microglial activation, perineuronal nets around parvalbumin-positive INs were partially disrupted in rTg4510 mice. Taken together, our data indicate that the excitability of cortical fast-spiking INs is decreased, possibly because of the disruption of perineuronal nets.

DOI： 10.1016/j.isci.2023.106342

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Limitations of human tau-expressing mouse models and novel approaches of mouse modeling for tauopathy. Reviewed International journal

Naruhiko Sahara, Rin Yanai

Frontiers in neuroscience 17 1149761 - 1149761 2023

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Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein are primarily neuropathological features of a number of neurodegenerative diseases, collectively termed tauopathy. There is no disease-modifying drug available for tauopathy except anti-amyloid antibody therapies for Alzheimer's disease. For tau-targeting therapy, experimental models recapitulating human tau pathologies are indispensable. However, there are limited numbers of animal models that display intracellular filamentous tau aggregations. At present, several lines of P301L/S mutant tau-expressing transgenic mice successfully developed neurofibrillary pathology in the central nervous system, while most non-mutant tau-expressing transgenic mice rarely developed tau pathology. Importantly, recent studies have revealed that transgenes disrupt the coding sequence of endogenous genes, resulting in deletions and/or structural variations at the insertion site. Although any impact on the pathogenesis of tauopathy is unknown, gene disruptions may affect age-related neurodegeneration including tangle formation and brain atrophy. Moreover, some mouse lines show strain-dependent pathological features. These limitations (FTDP-17 mutations, insertion/deletion mutations, and genetic background) are a major hindrance to the establishment of a precise disease model of tauopathy. In this review, we noticed both the utility and the pitfalls of current P301L/S mutant tau-expressing transgenic mice, and we propose future strategies of mouse modeling to replicate human tauopathies.

DOI： 10.3389/fnins.2023.1149761

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Multimodal analyses of a non-human primate model harboring mutant amyloid precursor protein transgenes driven by the human EF1α promoter. International journal

Sho Yoshimatsu, Fumiko Seki, Junko Okahara, Hirotaka Watanabe, Hiroki Sasaguri, Yawara Haga, Jun-ichi Hata, Tsukasa Sanosaka, Takashi Inoue, Takayuki Mineshige, Chia-Ying Lee, Haruka Shinohara, Yoko Kurotaki, Yuji Komaki, Noriyuki Kishi, Ayaka Y. Murayama, Yuji Nagai, Takafumi Minamimoto, Masafumi Yamamoto, Mayutaka Nakajima, Zhi Zhou, Akisa Nemoto, Tsukika Sato, Takeshi Ikeuchi, Naruhiko Sahara, Satoru Morimoto, Seiji Shiozawa, Takaomi C. Saido, Erika Sasaki, Hideyuki Okano

Neuroscience Research 185 49 - 61 2022.9

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Alzheimer's disease (AD) is the leading cause of dementia which afflicts tens of millions of people worldwide. Despite many scientific progresses to dissect the AD's molecular basis from studies on various mouse models, it has been suffered from evolutionary species differences. Here, we report generation of a non-human primate (NHP), common marmoset model ubiquitously expressing Amyloid-beta precursor protein (APP) transgenes with the Swedish (KM670/671NL) and Indiana (V717F) mutations. The transgene integration of generated two transgenic marmosets (TG1&TG2) was thoroughly investigated by genomic PCR, whole-genome sequencing, and fluorescence in situ hybridization. By reprogramming, we confirmed the validity of transgene expression in induced neurons in vitro. Moreover, we discovered structural changes in specific brain regions of transgenic marmosets by magnetic resonance imaging analysis, including in the entorhinal cortex and hippocampus. In immunohistochemistry, we detected increased Aβ plaque-like structures in TG1 brain at 7 years old, although evident neuronal loss or glial inflammation was not observed. Thus, this study summarizes our attempt to establish an NHP AD model. Although the transgenesis approach alone seemed not sufficient to fully recapitulate AD in NHPs, it may be beneficial for drug development and further disease modeling by combination with other genetically engineered models and disease-inducing approaches.

DOI： 10.1016/j.neures.2022.08.008

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A quantitative in vivo imaging platform for tracking pathological tau depositions and resultant neuronal death in a mouse model International journal

Taeko Kimura, Maiko Ono, Chie Seki, Kazuaki Sampei, Masafumi Shimojo, Kazunori Kawamura, Ming-Rong Zhang, Naruhiko Sahara, Yuhei Takado, Makoto Higuchi

European Journal of Nuclear Medicine and Molecular Imaging 49 ( 13 ) 4298 - 4311 2022.7

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Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

PURPOSE: Depositions of tau fibrils are implicated in diverse neurodegenerative disorders, including Alzheimer's disease, and precise assessments of tau pathologies and their impacts on neuronal survival are crucial for pursuing the neurodegenerative tau pathogenesis with and without potential therapies. We aimed to establish an in vivo imaging system to quantify tau accumulations with positron emission tomography (PET) and brain atrophy with volumetric MRI in rTg4510 transgenic mice modeling neurodegenerative tauopathies. METHODS: A total of 91 rTg4510 and non-transgenic control mice underwent PET with a tau radiotracer, 18F-PM-PBB3, and MRI at various ages (1.8-12.3 months). Using the cerebellum as reference, the radiotracer binding in target regions was estimated as standardized uptake value ratio (SUVR) and distribution volume ratio (DVR). Histopathological staining of brain sections derived from scanned animals was also conducted to investigate the imaging-neuropathology correlations. RESULTS: 18F-PM-PBB3 SUVR at 40-60 min in the neocortex, hippocampus, and striatum of rTg4510 mice agreed with DVR, became significantly different from control values around 4-5 months of age, and progressively and negatively correlated with age and local volumes, respectively. Neocortical SUVR also correlated with the abundance of tau inclusions labeled with PM-PBB3 fluorescence, Gallyas-Braak silver impregnation, and anti-phospho-tau antibodies in postmortem assays. The in vivo and ex vivo 18F-PM-PBB3 binding was blocked by non-radioactive PM-PBB3. 18F-PM-PBB3 yielded a 1.6-fold greater dynamic range for tau imaging than its ancestor, 11C-PBB3. CONCLUSION: Our imaging platform has enabled the quantification of tau depositions and consequent neuronal loss and is potentially applicable to the evaluation of candidate anti-tau and neuroprotective drugs.

DOI： 10.1007/s00259-022-05898-3

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Other Link： https://link.springer.com/article/10.1007/s00259-022-05898-3/fulltext.html
Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy. Reviewed International journal

Maiko Ono, Masaaki Komatsu, Bin Ji, Yuhei Takado, Masafumi Shimojo, Takeharu Minamihisamatsu, Eiji Warabi, Toru Yanagawa, Gen Matsumoto, Ichio Aoki, Nicholas M Kanaan, Tetsuya Suhara, Naruhiko Sahara, Makoto Higuchi

Aging cell 21 ( 7 ) e13615 2022.6

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Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Intracellular accumulation of filamentous tau aggregates with progressive neuronal loss is a common characteristic of tauopathies. Although the neurodegenerative mechanism of tau-associated pathology remains unclear, molecular elements capable of degrading and/or sequestering neurotoxic tau species may suppress neurodegenerative progression. Here, we provide evidence that p62/SQSTM1, a ubiquitinated cargo receptor for selective autophagy, acts protectively against neuronal death and neuroinflammation provoked by abnormal tau accumulation. P301S mutant tau transgenic mice (line PS19) exhibited accumulation of neurofibrillary tangles with localization of p62 mostly in the brainstem, but neuronal loss with few neurofibrillary tangles in the hippocampus. In the hippocampus of PS19 mice, the p62 level was lower compared to the brainstem, and punctate accumulation of phosphorylated tau unaccompanied by co-localization of p62 was observed. In PS19 mice deficient in p62 (PS19/p62-KO), increased accumulation of phosphorylated tau, acceleration of neuronal loss, and exacerbation of neuroinflammation were observed in the hippocampus as compared with PS19 mice. In addition, increase of abnormal tau and neuroinflammation were observed in the brainstem of PS19/p62-KO. Immunostaining and dot-blot analysis with an antibody selectively recognizing tau dimers and higher-order oligomers revealed that oligomeric tau species in PS19/p62-KO mice were significantly accumulated as compared to PS19 mice, suggesting the requirement of p62 to eliminate disease-related oligomeric tau species. Our findings indicated that p62 exerts neuroprotection against tau pathologies by eliminating neurotoxic tau species, suggesting that the manipulative p62 and selective autophagy may provide an intrinsic therapy for the treatment of tauopathy.

DOI： 10.1111/acel.13615

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Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology. International journal

Koyo Tsujikawa, Kohei Hamanaka, Yuichi Riku, Yuki Hattori, Norikazu Hara, Yohei Iguchi, Shinsuke Ishigaki, Atsushi Hashizume, Satoko Miyatake, Satomi Mitsuhashi, Yu Miyazaki, Mayumi Kataoka, Li Jiayi, Keizo Yasui, Satoshi Kuru, Haruki Koike, Kenta Kobayashi, Naruhiko Sahara, Norio Ozaki, Mari Yoshida, Akiyoshi Kakita, Yuko Saito, Yasushi Iwasaki, Akinori Miyashita, Takeshi Iwatsubo, Takeshi Ikeuchi, Takaki Miyata, Gen Sobue, Naomichi Matsumoto, Kentaro Sahashi, Masahisa Katsuno

Science advances 8 ( 21 ) eabm5029 2022.5

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While amyloid-β lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.

DOI： 10.1126/sciadv.abm5029

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PET-based classification of corticobasal syndrome. International journal

Yoshikazu Nakano, Hitoshi Shimada, Hitoshi Shinotoh, Shigeki Hirano, Kenji Tagai, Yasunori Sano, Yasuharu Yamamoto, Hironobu Endo, Kiwamu Matsuoka, Keisuke Takahata, Manabu Kubota, Yuhei Takado, Yasuyuki Kimura, Masanori Ichise, Maiko Ono, Naruhiko Sahara, Kazunori Kawamura, Ming-Rong Zhang, Satoshi Kuwabara, Tetsuya Suhara, Makoto Higuchi

Parkinsonism & related disorders 98 92 - 98 2022.4

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INTRODUCTION: Corticobasal degeneration (CBD) is the most common neuropathological substrate for clinically diagnosed corticobasal syndrome (CBS), while identifying CBD pathology in living individuals has been challenging. This study aimed to examine the capability of positron emission tomography (PET) to detect CBD-type tau depositions and neuropathological classification of CBS. METHODS: Sixteen CBS cases diagnosed by Cambridge's criteria and 12 cognitively healthy controls (HCs) underwent PET scans with 11C-PiB, 11C-PBB3, and 18F-FDG, along with T1-weighted magnetic resonance imaging. Amyloid positivity was assessed by visual inspection of 11C-PiB retentions. Tau positivity was judged by quantitative comparisons of 11C-PBB3 binding to HCs. RESULTS: Sixteen CBS cases consisted of two cases (13%) with amyloid and tau positivities indicative of Alzheimer's disease (AD) pathologies, 11 cases (69%) with amyloid negativity and tau positivity, and three cases (19%) with amyloid and tau negativities. Amyloid(-), tau(+) CBS cases showed increased retentions of 11C-PBB3 in the frontoparietal areas, basal ganglia, and midbrain, and reduced metabolism in the precentral gyrus and thalamus relative to HCs. The enhanced tau probe retentions in the frontal gray and white matters partially overlapped with metabolic deficits and atrophy and correlated with Clinical Dementia Rating scores. CONCLUSIONS: PET-based classification of CBS was in accordance with previous neuropathological reports on the prevalences of AD, non-AD tauopathies, and others in CBS. The current work suggests that 11C-PBB3-PET may assist the biological classification of CBS and understanding of links between CBD-type tau depositions and neuronal deteriorations leading to cognitive declines.

DOI： 10.1016/j.parkreldis.2022.04.015

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Endothelial expression of human amyloid precursor protein leads to amyloid β in the blood and induces cerebral amyloid angiopathy in knock-in mice. International journal

Yuriko Tachida, Saori Miura, Yui Muto, Hiroyuki Takuwa, Naruhiko Sahara, Akihiro Shindo, Yukio Matsuba, Takashi Saito, Naoyuki Taniguchi, Yasushi Kawaguchi, Hidekazu Tomimoto, Takaomi Saido, Shinobu Kitazume

The Journal of biological chemistry 298 ( 6 ) 101880 - 101880 2022.3

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The deposition of amyloid β (Aβ) in blood vessels of the brain, known as cerebral amyloid angiopathy (CAA), is observed in most Alzheimer's disease (AD) patients. Compared with the pathology of CAA in humans, the pathology in most mouse models of AD is not as evident, making it difficult to examine the contribution of CAA to the pathogenesis of AD. On the basis of biochemical analyses that showed blood levels of soluble amyloid precursor protein (sAPP) in rats and mice were markedly lower than those measured in human samples, we hypothesized that endothelial APP expression would be markedly lower in rodents, and subsequently generated mice that specifically express human wild type APP (APP770) in endothelial cells. The resulting EC-APP770+ mice exhibited increased levels of serum Aβ and sAPP, indicating that endothelial APP makes a critical contribution to blood Aβ levels. Even though aged EC-APP770+ mice did not exhibit Aβ deposition in the cortical blood vessels, crossing these animals with APP knock-in mice (AppNL-F/NL-F) led to an expanded CAA pathology, as evidenced by increased amounts of amyloid accumulated in the cortical blood vessels. These results highlight an overlooked interplay between neuronal and endothelial APP in brain vascular Aβ deposition. We propose that these EC-APP770+:AppNL-F/NL-F mice may be useful to study the basic molecular mechanisms behind the possible breakdown of the blood-brain barrier upon administration of anti-Aβ antibodies.

DOI： 10.1016/j.jbc.2022.101880

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Editorial: Translational imaging in neurodegenerative proteinopathies. International journal

Ruiqing Ni, Naruhiko Sahara, Bin Ji

Frontiers in neuroscience 16 952449 - 952449 2022

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DOI： 10.3389/fnins.2022.952449

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生体脳イメージングを用いたタウ凝集体を有する神経細胞の脳外排出メカニズムの実証

高橋真奈美, 田桑弘之, 漆畑拓弥, 下條雅文, 折原あすみ, 小野麻衣子, 高堂祐平, 冨田裕, 佐原成彦, 須原哲也, 樋口真人

脳循環代謝 33 ( 1 ) 121 - 121 2021.11

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Language：Japanese Publisher：(一社)日本脳循環代謝学会

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Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model. International journal

Hideaki Sato, Yuhei Takado, Sakiko Toyoda, Masako Tsukamoto-Yasui, Keiichiro Minatohara, Hiroyuki Takuwa, Takuya Urushihata, Manami Takahashi, Masafumi Shimojo, Maiko Ono, Jun Maeda, Asumi Orihara, Naruhiko Sahara, Ichio Aoki, Sachise Karakawa, Muneki Isokawa, Noriko Kawasaki, Mika Kawasaki, Satoko Ueno, Mayuka Kanda, Mai Nishimura, Katsuya Suzuki, Akira Mitsui, Kenji Nagao, Akihiko Kitamura, Makoto Higuchi

Science advances 7 ( 43 ) eabd5046 2021.10

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[Figure: see text].

DOI： 10.1126/sciadv.abd5046

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A genetically targeted reporter for PET imaging of deep neuronal circuits in mammalian brains. International journal

Masafumi Shimojo, Maiko Ono, Hiroyuki Takuwa, Koki Mimura, Yuji Nagai, Masayuki Fujinaga, Tatsuya Kikuchi, Maki Okada, Chie Seki, Masaki Tokunaga, Jun Maeda, Yuhei Takado, Manami Takahashi, Takeharu Minamihisamatsu, Ming-Rong Zhang, Yutaka Tomita, Norihiro Suzuki, Anton Maximov, Tetsuya Suhara, Takafumi Minamimoto, Naruhiko Sahara, Makoto Higuchi

The EMBO journal 40 ( 22 ) e107757 2021.10

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Positron emission tomography (PET) allows biomolecular tracking but PET monitoring of brain networks has been hampered by a lack of suitable reporters. Here, we take advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP, to facilitate in vivo imaging in the brain. Peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expression in mice. This technique can be used to the visualize neuronal circuit activity elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR-PET allows mapping of neuronal projections in non-human primate brains, demonstrating the applicability of ecDHFR-based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET studies of turnover and self-assembly of proteins tagged with ecDHFR mutants. These results establish opportunities for a broad spectrum of previously unattainable PET analyses of mammalian brain circuits at the molecular level.

DOI： 10.15252/embj.2021107757

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MRS-measured glutamate versus GABA reflects excitatory versus inhibitory neural activities in awake mice. International journal

Yuhei Takado, Hiroyuki Takuwa, Kazuaki Sampei, Takuya Urushihata, Manami Takahashi, Masafumi Shimojo, Shoko Uchida, Nobuhiro Nitta, Sayaka Shibata, Keisuke Nagashima, Yoshihiro Ochi, Maiko Ono, Jun Maeda, Yutaka Tomita, Naruhiko Sahara, Jamie Near, Ichio Aoki, Kazuhisa Shibata, Makoto Higuchi

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 42 ( 1 ) 271678X211045449 - 212 2021.9

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To assess if magnetic resonance spectroscopy (MRS)-measured Glutamate (Glu) and GABA reflect excitatory and inhibitory neural activities, respectively, we conducted MRS measurements along with two-photon mesoscopic imaging of calcium signals in excitatory and inhibitory neurons of living, unanesthetized mice. For monitoring stimulus-driven activations of a brain region, MRS signals and mesoscopic neural activities were measured during two consecutive sessions of 15-min prolonged sensory stimulations. In the first session, putative excitatory neuronal activities were increased, while inhibitory neuronal activities remained at the baseline level. In the second half, while excitatory neuronal activities remained elevated, inhibitory neuronal activities were significantly enhanced. We assessed regional neurochemical statuses by measuring MRS signals, which were overall in accordance with the neural activities, and neuronal activities and neurochemical statuses in a mouse model of Dravet syndrome under resting condition. Mesoscopic assessments showed that activities of inhibitory neurons in the cortex were diminished relative to wild-type mice in contrast to spared activities of excitatory neurons. Consistent with these observations, the Dravet model exhibited lower concentrations of GABA than wild-type controls. Collectively, the current investigations demonstrate that MRS-measured Glu and GABA can reflect spontaneous and stimulated activities of neurons producing and releasing these neurotransmitters in an awake condition.

DOI： 10.1177/0271678X211045449

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Correction to: Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607 (Acta Neuropathologica, (2021), 141, 5, (697-708), 10.1007/s00401-021-02294-3) International journal

Yang Shi, Alexey G. Murzin, Benjamin Falcon, Alexander Epstein, Jonathan Machin, Paul Tempest, Kathy L. Newell, Ruben Vidal, Holly J. Garringer, Naruhiko Sahara, Makoto Higuchi, Bernardino Ghetti, Ming-Kuei Jang, Sjors H. W. Scheres, Michel Goedert

Acta Neuropathologica 141 ( 6 ) 983 - 983 2021.6

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Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media Deutschland GmbH

DOI： 10.1007/s00401-021-02303-5

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Neuroprotective effect of mitochondrial translocator protein ligand in a mouse model of tauopathy. International journal

Lauren H Fairley, Naruhiko Sahara, Ichio Aoki, Bin Ji, Tetsuya Suhara, Makoto Higuchi, Anna M Barron

Journal of neuroinflammation 18 ( 1 ) 76 - 76 2021.3

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BACKGROUND: The translocator protein (TSPO) has been identified as a positron emission tomography (PET)-visible biomarker of inflammation and promising immunotherapeutic target for the treatment of Alzheimer's disease (AD). While TSPO ligands have been shown to reduce the accumulation of the toxic Alzheimer's beta-amyloid peptide, their effect on tau pathology has not yet been investigated. To address this, we analyzed the effects of TSPO ligand, Ro5-4864, on the progression of neuropathology in rTg4510 tau transgenic mice (TauTg). METHODS: Brain atrophy, tau accumulation, and neuroinflammation were assessed longitudinally using volumetric magnetic resonance imaging, tau-PET, and TSPO-PET, respectively. In vivo neuroimaging results were confirmed by immunohistochemistry for markers of neuronal survival (NeuN), tauopathy (AT8), and inflammation (TSPO, ionized calcium-binding adaptor molecule 1 or IBA-1, and complement component 1q or C1q) in brain sections from scanned mice. RESULTS: TSPO ligand treatment attenuated brain atrophy and hippocampal neuronal loss in the absence of any detected effect on tau depositions. Atrophy and neuronal loss were strongly associated with in vivo inflammatory signals measured by TSPO-PET, IBA-1, and levels of C1q, a regulator of the complement cascade. In vitro studies confirmed that the TSPO ligand Ro5-4864 reduces C1q expression in a microglial cell line in response to inflammation, reduction of which has been shown in previous studies to protect synapses and neurons in models of tauopathy. CONCLUSIONS: These findings support a protective role for TSPO ligands in tauopathy, reducing neuroinflammation, neurodegeneration, and brain atrophy.

DOI： 10.1186/s12974-021-02122-1

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Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607. International journal

Yang Shi, Alexey G Murzin, Benjamin Falcon, Alexander Epstein, Jonathan Machin, Paul Tempest, Kathy L Newell, Ruben Vidal, Holly J Garringer, Naruhiko Sahara, Makoto Higuchi, Bernardino Ghetti, Ming-Kuei Jang, Sjors H W Scheres, Michel Goedert

Acta neuropathologica 141 ( 5 ) 697 - 708 2021.3

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Tau and Aβ assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.

DOI： 10.1007/s00401-021-02294-3

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Detection of Alzheimer's disease-related neuroinflammation by a PET ligand selective for glial versus vascular translocator protein. International journal

Bin Ji, Maiko Ono, Tomoteru Yamasaki, Masayuki Fujinaga, Ming-Rong Zhang, Chie Seki, Ichio Aoki, Seiji Kito, Makoto Sawada, Tetsuya Suhara, Naruhiko Sahara, Makoto Higuchi

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 41 ( 8 ) 271678X21992457 - 2089 2021.2

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A substantial and constitutive expression of translocator protein (TSPO) in cerebral blood vessels hampers the sensitive detection of neuroinflammation characterized by greatly induced TSPO expression in activated glia. Here, we conducted in vivo positron emission tomography (PET) and in vitro autoradiographic imaging of normal and TSPO-deficient mouse brains to compare the binding properties of 18F-FEBMP, a relatively novel TSPO radioligand developed for human studies based on its insensitivity to a common polymorphism, with 11C-PK11195, as well as other commonly used TSPO radioligands including 11C-PBR28, 11C-Ac5216 and 18F-FEDAA1106. TSPO in cerebral vessels of normal mice was found to provide a major binding site for 11C-PK11195, 11C-PBR28 and 18F-FEDAA1106, in contrast to no overt specific binding of 18F-FEBMP and 11C-Ac5216 to this vascular component. In addition, 18F-FEBMP yielded PET images of microglial TSPO with a higher contrast than 11C-PK11195 in a tau transgenic mouse modeling Alzheimer's disease (AD) and allied neurodegenerative tauopathies. Moreover, TSPO expression examined by immunoblotting was significantly increased in AD brains compared with healthy controls, and was well correlated with the autoradiographic binding of 18F-FEBMP but not 11C-PK11195. Our findings support the potential advantage of comparatively glial TSPO-selective radioligands such as 18F-FEBMP for PET imaging of inflammatory glial cells.

DOI： 10.1177/0271678X21992457

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High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies. Reviewed International journal

Kenji Tagai, Maiko Ono, Manabu Kubota, Soichiro Kitamura, Keisuke Takahata, Chie Seki, Yuhei Takado, Hitoshi Shinotoh, Yasunori Sano, Yasuharu Yamamoto, Kiwamu Matsuoka, Hiroyuki Takuwa, Masafumi Shimojo, Manami Takahashi, Kazunori Kawamura, Tatsuya Kikuchi, Maki Okada, Haruhiko Akiyama, Hisaomi Suzuki, Mitsumoto Onaya, Takahiro Takeda, Kimihito Arai, Nobutaka Arai, Nobuyuki Araki, Yuko Saito, John Q Trojanowski, Virginia M Y Lee, Sushil K Mishra, Yoshiki Yamaguchi, Yasuyuki Kimura, Masanori Ichise, Yutaka Tomita, Ming-Rong Zhang, Tetsuya Suhara, Masahiro Shigeta, Naruhiko Sahara, Makoto Higuchi, Hitoshi Shimada

Neuron 109 ( 1 ) 42 - 58 2021.1

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A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer's disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of 18F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick's disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.

DOI： 10.1016/j.neuron.2020.09.042

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Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease. Reviewed International journal

Akira Sobue, Okiru Komine, Yuichiro Hara, Fumito Endo, Hiroyuki Mizoguchi, Seiji Watanabe, Shigeo Murayama, Takashi Saito, Takaomi C Saido, Naruhiko Sahara, Makoto Higuchi, Tomoo Ogi, Koji Yamanaka

Acta neuropathologica communications 9 ( 1 ) 1 - 1 2021.1

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Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

DOI： 10.1186/s40478-020-01099-x

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Distinct microglial response against Alzheimer's amyloid and tau pathologies characterized by P2Y12 receptor. Reviewed International journal

Jun Maeda, Takeharu Minamihisamatsu, Masafumi Shimojo, Xiaoyun Zhou, Maiko Ono, Yukio Matsuba, Bin Ji, Hideki Ishii, Masanao Ogawa, Hiroyasu Akatsu, Daita Kaneda, Yoshio Hashizume, John L Robinson, Virginia M-Y Lee, Takashi Saito, Takaomi C Saido, John Q Trojanowski, Ming-Rong Zhang, Tetsuya Suhara, Makoto Higuchi, Naruhiko Sahara

Brain communications 3 ( 1 ) fcab011 2021

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Microglia are the resident phagocytes of the central nervous system, and microglial activation is considered to play an important role in the pathogenesis of neurodegenerative diseases. Recent studies with single-cell RNA analysis of CNS cells in Alzheimer's disease and diverse other neurodegenerative conditions revealed that the transition from homeostatic microglia to disease-associated microglia was defined by changes of gene expression levels, including down-regulation of the P2Y12 receptor gene (P2Y12R). However, it is yet to be clarified in Alzheimer's disease brains whether and when this down-regulation occurs in response to amyloid-β and tau depositions, which are core pathological processes in the disease etiology. To further evaluate the significance of P2Y12 receptor alterations in the neurodegenerative pathway of Alzheimer's disease and allied disorders, we generated an anti-P2Y12 receptor antibody and examined P2Y12 receptor expressions in the brains of humans and model mice bearing amyloid-β and tau pathologies. We observed that the brains of both Alzheimer's disease and non-Alzheimer's disease tauopathy patients and tauopathy model mice (rTg4510 and PS19 mouse lines) displayed declined microglial P2Y12 receptor levels in regions enriched with tau inclusions, despite an increase in the total microglial population. Notably, diminution of microglial immunoreactivity with P2Y12 receptor was noticeable prior to massive accumulations of phosphorylated tau aggregates and neurodegeneration in rTg4510 mouse brains, despite a progressive increase of total microglial population. On the other hand, Iba1-positive microglia encompassing compact and dense-cored amyloid-β plaques expressed P2Y12 receptor at varying levels in amyloid precursor protein (APP) mouse models (APP23 and AppNL-F/NL-F mice). By contrast, neuritic plaques in Alzheimer's disease brains were associated with P2Y12 receptor-negative microglia. These data suggest that the down-regulation of microglia P2Y12 receptor, which is characteristic of disease-associated microglia, is intimately associated with tau rather than amyloid-β pathologies from an early stage and could be a sensitive index for neuroinflammatory responses to Alzheimer's disease-related neurodegenerative processes.

DOI： 10.1093/braincomms/fcab011

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Pick's Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling. Reviewed International journal

Sushil K Mishra, Yoshiki Yamaguchi, Makoto Higuchi, Naruhiko Sahara

International journal of molecular sciences 22 ( 1 ) 2020.12

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Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

In recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer's disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related dementias, such as Pick's disease, have not been widely explored. To design disease-specific and tau-selective PET tracers, it is important to determine where and how PET tracers bind to tau filaments. In this paper, we present the first molecular modelling study on PET probe binding to the structured core of tau filaments from a patient with Pick's disease (TauPiD). We have used docking, molecular dynamics simulations, binding-affinity and tunnel calculations to explore TauPiD binding sites, binding modes, and binding energies of PET probes (AV-1451, MK-6240, PBB3, PM-PBB3, THK-5351 and PiB) with TauPiD. The probes bind to TauPiD at multiple surface binding sites as well as in a cavity binding site. The probes show unique surface binding patterns, and, out of them all, PM-PBB3 proves to bind the strongest. The findings suggest that our computational workflow of structural and dynamic details of the tau filaments has potential for the rational design of TauPiD specific PET tracers.

DOI： 10.3390/ijms22010349

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Tracking tau fibrillogenesis and consequent primary phagocytosis of neurons mediated by microglia in a living tauopathy model

Hiroyuki Takuwa, Asumi Orihara, Yuhei Takado, Takuya Urushihata, Masafumi Shimojo, Ai Ishikawa, Manami Takahashi, Anna M. Barron, Maiko Ono, Jun Maeda, Kazuto Masamoto, Hiroyasu Akatsu, Aviva M. Tolkovsky, Bin Ji, Yutaka Tomita, Hiroshi Ito, Ming-Rong Zhang, Michel Goedert, Maria Grazia Spillantini, Virginia M. -Y. Lee, John Q. Trojanowski, Taketoshi Maehara, Tetsuya Suhara, Naruhiko Sahara, Makoto Higuchi

2020.11

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Publisher：Cold Spring Harbor Laboratory

ABSTRACT

Fibrillary tau pathologies have been implicated in Alzheimer’s and allied neurodegenerative diseases, while mechanisms by which neurons bearing tau tangles die remain enigmatic. To address this issue, we pursued tau and related key pathologies macroscopically by PET and MRI and microscopically by intravital two-photon laser optics. Time-course macroscopic assays of tau transgenic mice demonstrated intimate associations of tau deposition and increase of an inflammatory microglial marker, translocator protein (TSPO), with regional brain atrophy. Longitudinal microscopy of these mice revealed a rapid turnover of tau lesions resulting from continuous generation of new tau aggregates followed by loss of neurons and their fibrillar contents. This technology also allowed the capturing of the disappearance of tangle-bearing neurons several days after being engulfed by activated microglia. Notably, a therapeutic TSPO ligand profoundly suppressed the mobility and phagocytotic activity of microglia and improved neuronal survival in this model, supporting the involvement of primary phagocytosis of viable neurons by microglia in tau-primed neuronal death. Finally, partial depletion of microglia revealed roles of immune factors, MFG-E8 and C1q, as ‘eat-me’ signals for an immediate attraction of phagocytic microglia towards the elimination of tangle-loaded neurons.

DOI： 10.1101/2020.11.04.368977

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進行性核上性麻痺における前部帯状回の乳酸高値は前頭葉機能障害と関連する

高堂裕平, 互健二, 松岡究, 篠遠仁, 佐野康徳, 高畑圭輔, 久保田学, 小野麻衣子, 佐原成彦, 小畠隆行, 河村和紀, 張明栄, 須原哲也, 島田斉, 樋口真人

臨床神経学 60 ( Suppl. ) S338 - S338 2020.11

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生体脳イメージングによる病原性蛋白質の脳外排出メカニズムの解明

高橋真奈美, 田桑弘之, 漆畑拓弥, 下條雅文, 冨田裕, 中原仁, 佐原成彦, 樋口真人

脳循環代謝 32 ( 1 ) 128 - 128 2020.11

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認知症CPC「認知症にかかわる医師のための臨床神経病理カンファレンス」急速に運動・認知機能障害が進行し、もの忘れ外来受診後経過3年で死亡した83歳女性剖検例

金田大太, 松原知康, 石井賢二, 徳丸阿耶, 島田斉, 佐原成彦, 須原哲也, 村山繁雄, 齊藤祐子

Dementia Japan 34 ( 4 ) 470 - 470 2020.10

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In vivo positron emission tomography imaging of mitochondrial abnormalities in a mouse model of tauopathy. Reviewed International journal

Anna M Barron, Bin Ji, Masayuki Fujinaga, Ming-Rong Zhang, Tetsuya Suhara, Naruhiko Sahara, Ichio Aoki, Hideo Tsukada, Makoto Higuchi

Neurobiology of aging 94 140 - 148 2020.10

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Damaged mitochondria may be one of the earliest manifestations of Alzheimer's disease. Because oxidative phosphorylation is a primary source of neuronal energy, unlike glycolysis-dependent energy production in inflamed glia, mitochondrial respiration could provide a selective biomarker of neuronal deterioration in Alzheimer's disease. Here we used a recently developed positron emission tomography (PET) probe targeting mitochondrial complex I (MC-I), 18F-BCPP-EF, to non-invasively visualize mitochondrial abnormalities in the brains of tau transgenic mice (rTg4510). Tauopathy and neuroinflammation were visualized by PET using a tau probe 11C-PBB3 and a translocator protein probe, 18F-FEBMP, respectively. A marked reduction in 18F-BCPP-EF uptake was observed in hippocampal and forebrain regions of tau transgenic mice, colocalizing with regions of tauopathy, neuronal damage, and neuroinflammation. MC-I signals were highly correlated with atrophy assayed by magnetic resonance imaging, but negatively associated with inflammatory signals, indicating that neuronal metabolic signals measured by MC-I PET were robust to inflammatory interference. MC-I may be a useful imaging biomarker to detect neuronal damage and metabolic changes with minimal interference from concomitant glial hypermetabolism.

DOI： 10.1016/j.neurobiolaging.2020.05.003

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タウオパチーモデルマウスにおけるアミノ酸組成物摂取による神経変性抑止効果

高堂裕平, 佐藤英明, 豊田早紀子, 安居昌子, 漆原圭一郎, 田桑弘之, 漆畑拓弥, 高橋真奈美, 下條雅文, 小野麻衣子, 前田純, 佐原成彦, 青木伊知男, 川崎則子, 神田麻優香, 西村麻依, 長尾健児, 北村明彦, 樋口真人

Dementia Japan 34 ( 4 ) 530 - 530 2020.10

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Selective Disruption of Inhibitory Synapses Leading to Neuronal Hyperexcitability at an Early Stage of Tau Pathogenesis in a Mouse Model. Reviewed International journal

Masafumi Shimojo, Hiroyuki Takuwa, Yuhei Takado, Masaki Tokunaga, Satoshi Tsukamoto, Keiichiro Minatohara, Maiko Ono, Chie Seki, Jun Maeda, Takuya Urushihata, Takeharu Minamihisamatsu, Ichio Aoki, Kazunori Kawamura, Ming-Rong Zhang, Tetsuya Suhara, Naruhiko Sahara, Makoto Higuchi

The Journal of neuroscience : the official journal of the Society for Neuroscience 40 ( 17 ) 3491 - 3501 2020.4

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Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [11C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[11C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer in vivo indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies.SIGNIFICANCE STATEMENT In this study, we examined the in vivo status of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by PET imaging with (E)-[11C]ABP688 and [11C]flumazenil, respectively. We identified inhibitory synapse as being significantly dysregulated before brain atrophy at 2 months of age, while excitatory synapse stayed relatively intact at this stage. In line with this observation, postmortem assessment of brain tissues demonstrated selective attenuation of inhibitory synaptic constituents accompanied by the upregulation of cFos before the formation of tau pathology in the forebrain at young ages. Our findings indicate that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit constitutes the critical early pathophysiology of tauopathy.

DOI： 10.1523/JNEUROSCI.2880-19.2020

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Nasal vaccine delivery attenuates brain pathology and cognitive impairment in tauopathy model mice. International journal

Hiroki Takeuchi, Keiko Imamura, Bin Ji, Kayoko Tsukita, Takako Enami, Keizo Takao, Tsuyoshi Miyakawa, Masato Hasegawa, Naruhiko Sahara, Nobuhisa Iwata, Makoto Inoue, Hideo Hara, Takeshi Tabira, Maiko Ono, John Q Trojanowski, Virginia M-Y Lee, Ryosuke Takahashi, Tetsuya Suhara, Makoto Higuchi, Haruhisa Inoue

NPJ vaccines 5 ( 1 ) 28 - 28 2020.3

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Pathological aggregates of tau proteins accumulate in the brains of neurodegenerative tauopathies including Alzheimer's disease and frontotemporal lobar degeneration (FTLD-tau). Although immunotherapies of these disorders against tau are emerging, it is unknown whether nasal delivery, which offers many benefits over traditional approaches to vaccine administration, is effective or not for tauopathy. Here, we developed vaccination against a secreted form of pathological tau linked to FTLD-tau using a Sendai virus (SeV) vector infectious to host nasal mucosa, a key part of the immune system. Tau vaccines given as nasal drops induced tissue tau-immunoreactive antibody production and ameliorated cognitive impairment in FTLD-tau model mice. In vivo imaging and postmortem neuropathological assays demonstrated the suppression of phosphorylated tau accumulation, neurotoxic gliosis, and neuronal loss in the hippocampus of immunized mice. These findings suggest that nasal vaccine delivery may provide a therapeutic opportunity for a broad range of populations with human tauopathy.

DOI： 10.1038/s41541-020-0172-y

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Nasal vaccine delivery attenuates brain pathology and cognitive impairment in tauopathy model mice. Reviewed International journal

Hiroki Takeuchi, Keiko Imamura, Bin Ji, Kayoko Tsukita, Takako Enami, Keizo Takao, Tsuyoshi Miyakawa, Masato Hasegawa, Naruhiko Sahara, Nobuhisa Iwata, Makoto Inoue, Hideo Hara, Takeshi Tabira, Maiko Ono, John Q Trojanowski, Virginia M-Y Lee, Ryosuke Takahashi, Tetsuya Suhara, Makoto Higuchi, Haruhisa Inoue

NPJ vaccines 5 ( 1 ) 28 - 28 2020

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Language：English Publishing type：Research paper (scientific journal)

Pathological aggregates of tau proteins accumulate in the brains of neurodegenerative tauopathies including Alzheimer's disease and frontotemporal lobar degeneration (FTLD-tau). Although immunotherapies of these disorders against tau are emerging, it is unknown whether nasal delivery, which offers many benefits over traditional approaches to vaccine administration, is effective or not for tauopathy. Here, we developed vaccination against a secreted form of pathological tau linked to FTLD-tau using a Sendai virus (SeV) vector infectious to host nasal mucosa, a key part of the immune system. Tau vaccines given as nasal drops induced tissue tau-immunoreactive antibody production and ameliorated cognitive impairment in FTLD-tau model mice. In vivo imaging and postmortem neuropathological assays demonstrated the suppression of phosphorylated tau accumulation, neurotoxic gliosis, and neuronal loss in the hippocampus of immunized mice. These findings suggest that nasal vaccine delivery may provide a therapeutic opportunity for a broad range of populations with human tauopathy.

DOI： 10.1038/s41541-020-0172-y

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Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs. Reviewed International journal

Mari Nakamura, Seiji Shiozawa, Daisuke Tsuboi, Mutsuki Amano, Hirotaka Watanabe, Sumihiro Maeda, Taeko Kimura, Sho Yoshimatsu, Fumihiko Kisa, Celeste M Karch, Tomohiro Miyasaka, Akihiko Takashima, Naruhiko Sahara, Shin-Ichi Hisanaga, Takeshi Ikeuchi, Kozo Kaibuchi, Hideyuki Okano

Stem cell reports 13 ( 4 ) 684 - 699 2019.10

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Mutations in the microtubule-associated protein tau (MAPT) gene are known to cause familial frontotemporal dementia (FTD). The R406W tau mutation is a unique missense mutation whose patients have been reported to exhibit Alzheimer's disease (AD)-like phenotypes rather than the more typical FTD phenotypes. In this study, we established patient-derived induced pluripotent stem cell (iPSC) models to investigate the disease pathology induced by the R406W mutation. We generated iPSCs from patients and established isogenic lines using CRISPR/Cas9. The iPSCs were induced into cerebral organoids, which were dissociated into cortical neurons with high purity. In this neuronal culture, the mutant tau protein exhibited reduced phosphorylation levels and was increasingly fragmented by calpain. Furthermore, the mutant tau protein was mislocalized and the axons of the patient-derived neurons displayed morphological and functional abnormalities, which were rescued by microtubule stabilization. The findings of our study provide mechanistic insight into tau pathology and a potential for therapeutic intervention.

DOI： 10.1016/j.stemcr.2019.08.011

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PET-detectable tau pathology correlates with long-term neuropsychiatric outcomes in patients with traumatic brain injury. Reviewed International journal

Keisuke Takahata, Yasuyuki Kimura, Naruhiko Sahara, Shunsuke Koga, Hitoshi Shimada, Masanori Ichise, Fumie Saito, Sho Moriguchi, Soichiro Kitamura, Manabu Kubota, Satoshi Umeda, Fumitoshi Niwa, Jin Mizushima, Yoko Morimoto, Michitaka Funayama, Hajime Tabuchi, Kevin F Bieniek, Kazunori Kawamura, Ming-Rong Zhang, Dennis W Dickson, Masaru Mimura, Motoichiro Kato, Tetsuya Suhara, Makoto Higuchi

Brain : a journal of neurology 142 ( 10 ) 3265 - 3279 2019.10

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Tau deposits is a core feature of neurodegenerative disorder following traumatic brain injury (TBI). Despite ample evidence from post-mortem studies demonstrating exposure to both mild-repetitive and severe TBIs are linked to tau depositions, associations of topology of tau lesions with late-onset psychiatric symptoms due to TBI have not been explored. To address this issue, we assessed tau deposits in long-term survivors of TBI by PET with 11C-PBB3, and evaluated those associations with late-life neuropsychiatric outcomes. PET data were acquired from 27 subjects in the chronic stage following mild-repetitive or severe TBI and 15 healthy control subjects. Among the TBI patients, 14 were diagnosed as having late-onset symptoms based on the criteria of traumatic encephalopathy syndrome. For quantification of tau burden in TBI brains, we calculated 11C-PBB3 binding capacity (cm3), which is a summed voxel value of binding potentials (BP*ND) multiplied by voxel volume. Main outcomes of the present study were differences in 11C-PBB3 binding capacity between groups, and the association of regional 11C-PBB3 binding capacity with neuropsychiatric symptoms. To confirm 11C-PBB3 binding to tau deposits in TBI brains, we conducted in vitro PBB3 fluorescence and phospho-tau antibody immunofluorescence labelling of brain sections of chronic traumatic encephalopathy obtained from the Brain Bank. Our results showed that patients with TBI had higher 11C-PBB3 binding capacities in the neocortical grey and white matter segments than healthy control subjects. Furthermore, TBI patients with traumatic encephalopathy syndrome showed higher 11C-PBB3 binding capacity in the white matter segment than those without traumatic encephalopathy syndrome, and regional assessments revealed that subgroup difference was also significant in the frontal white matter. 11C-PBB3 binding capacity in the white matter segment correlated with the severity of psychosis. In vitro assays demonstrated PBB3-positive tau inclusions at the depth of neocortical sulci, confirming 11C-PBB3 binding to tau lesions. In conclusion, increased 11C-PBB3 binding capacity is associated with late-onset neuropsychiatric symptoms following TBI, and a close correlation was found between psychosis and 11C-PBB3 binding capacity in the white matter.

DOI： 10.1093/brain/awz238

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Tau isoform expression and phosphorylation in marmoset brains. Reviewed International journal

Govinda Sharma, Anni Huo, Taeko Kimura, Seiji Shiozawa, Reona Kobayashi, Naruhiko Sahara, Minaka Ishibashi, Shinsuke Ishigaki, Taro Saito, Kanae Ando, Shigeo Murayama, Masato Hasegawa, Gen Sobue, Hideyuki Okano, Shin-Ichi Hisanaga

The Journal of biological chemistry 294 ( 30 ) 11433 - 11444 2019.7

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Tau is a microtubule-associated protein expressed in neuronal axons. Hyperphosphorylated tau is a major component of neurofibrillary tangles, a pathological hallmark of Alzheimer's disease (AD). Hyperphosphorylated tau aggregates are also found in many neurodegenerative diseases, collectively referred to as "tauopathies," and tau mutations are associated with familial frontotemporal lobar degeneration (FTLD). Previous studies have generated transgenic mice with mutant tau as tauopathy models, but nonhuman primates, which are more similar to humans, may be a better model to study tauopathies. For example, the common marmoset is poised as a nonhuman primate model for investigating the etiology of age-related neurodegenerative diseases. However, no biochemical studies of tau have been conducted in marmoset brains. Here, we investigated several important aspects of tau, including expression of different tau isoforms and its phosphorylation status, in the marmoset brain. We found that marmoset tau does not possess the "primate-unique motif" in its N-terminal domain. We also discovered that the tau isoform expression pattern in marmosets is more similar to that of mice than that of humans, with adult marmoset brains expressing only four-repeat tau isoforms as in adult mice but unlike in adult human brains. Of note, tau in brains of marmoset newborns was phosphorylated at several sites associated with AD pathology. However, in adult marmoset brains, much of this phosphorylation was lost, except for Ser-202 and Ser-404 phosphorylation. These results reveal key features of tau expression and phosphorylation in the marmoset brain, a potentially useful nonhuman primate model of neurodegenerative diseases.

DOI： 10.1074/jbc.RA119.008415

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Association between Brain and Plasma Glutamine Levels in Healthy Young Subjects Investigated by MRS and LC/MS. Reviewed International journal

Yuhei Takado, Naoto Sato, Yuta Kanbe, Moyoko Tomiyasu, Lijing Xin, Jamie Near, Kohki Yoshikawa, Naruhiko Sahara, Tatsuya Higashi, Tetsuya Suhara, Makoto Higuchi, Takayuki Obata

Nutrients 11 ( 7 ) 2019.7

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DOI： 10.3390/nu11071649

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Author Correction: Tau binding protein CAPON induces tau aggregation and neurodegeneration. Reviewed International journal

Shoko Hashimoto, Yukio Matsuba, Naoko Kamano, Naomi Mihira, Naruhiko Sahara, Jiro Takano, Shin-Ichi Muramatsu, Takaomi C Saido, Takashi Saito

Nature communications 10 ( 1 ) 2964 - 2964 2019.7

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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

DOI： 10.1038/s41467-019-10990-8

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Tau binding protein CAPON induces tau aggregation and neurodegeneration. Reviewed International journal

Shoko Hashimoto, Yukio Matsuba, Naoko Kamano, Naomi Mihira, Naruhiko Sahara, Jiro Takano, Shin-Ichi Muramatsu, Takaomi C Saido, Takashi Saito

Nature communications 10 ( 1 ) 2394 - 2394 2019.6

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To understand the molecular processes that link Aβ amyloidosis, tauopathy and neurodegeneration, we screened for tau-interacting proteins by immunoprecipitation/LC-MS. We identified the carboxy-terminal PDZ ligand of nNOS (CAPON) as a novel tau-binding protein. CAPON is an adaptor protein of neuronal nitric oxide synthase (nNOS), and activated by the N-methyl-D-aspartate receptor. We observed accumulation of CAPON in the hippocampal pyramidal cell layer in the AppNL-G-F -knock-in (KI) brain. To investigate the effect of CAPON accumulation on Alzheimer's disease (AD) pathogenesis, CAPON was overexpressed in the brain of AppNL-G-F mice crossbred with MAPT (human tau)-KI mice. This produced significant hippocampal atrophy and caspase3-dependent neuronal cell death in the CAPON-expressing hippocampus, suggesting that CAPON accumulation increases neurodegeneration. CAPON expression also induced significantly higher levels of phosphorylated, oligomerized and insoluble tau. In contrast, CAPON deficiency ameliorated the AD-related pathological phenotypes in tauopathy model. These findings suggest that CAPON could be a druggable AD target.

DOI： 10.1038/s41467-019-10278-x

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In vivo binding of a tau imaging probe, [11 C]PBB3, in patients with progressive supranuclear palsy. Reviewed International journal

Hironobu Endo, Hitoshi Shimada, Naruhiko Sahara, Maiko Ono, Shunsuke Koga, Soichiro Kitamura, Fumitoshi Niwa, Shigeki Hirano, Yasuyuki Kimura, Masanori Ichise, Hitoshi Shinotoh, Ming Rong Zhang, Satoshi Kuwabara, Dennis W Dickson, Tatsushi Toda, Tetsuya Suhara, Makoto Higuchi

Movement disorders : official journal of the Movement Disorder Society 34 ( 5 ) 744 - 754 2019.5

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DOI： 10.1002/mds.27643

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Clinical heterogeneity of frontotemporal dementia and Parkinsonism linked to chromosome 17 caused by MAPT N279K mutation in relation to tau positron emission tomography features. Reviewed International journal

Aya Ikeda, Hitoshi Shimada, Kenya Nishioka, Masashi Takanashi, Arisa Hayashida, Yuanzhe Li, Hiroyo Yoshino, Manabu Funayama, Yuji Ueno, Taku Hatano, Naruhiko Sahara, Tetsuya Suhara, Makoto Higuchi, Nobutaka Hattori

Movement disorders : official journal of the Movement Disorder Society 34 ( 4 ) 568 - 574 2019.4

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BACKGROUND: While mechanistic links between tau abnormalities and neurodegeneration have been proven in frontotemporal dementia and parkinsonism linked to chromosome 17 caused by MAPT mutations, variability of the tau pathogenesis and its relation to clinical progressions in the same MAPT mutation carriers are yet to be clarified. OBJECTIVES: The present study aimed to analyze clinical profiles, tau accumulations, and their correlations in 3 kindreds with frontotemporal dementia and parkinsonism linked to chromosome 17 attributed to the MAPT N279K mutation. METHODS: Four patients with N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT underwent [11 C]PBB3-PET to estimate regional tau loads. RESULTS: Haplotype assays revealed that these kindreds originated from a single founder. Despite homogeneity of the disease-causing MAPT allele, clinical progression was more rapid in 2 kindreds than in the other. The kindred with slow progression showed mild tau depositions, mostly confined to the midbrain and medial temporal areas. In contrast, kindreds with rapid progression showed profoundly increased [11 C]PBB3 binding in widespread regions from an early disease stage. CONCLUSIONS: [11 C]PBB3-PET can capture four-repeat tau pathologies characteristic of N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT. Our findings indicate that, in addition to the mutated MAPT allele, genetic and/or epigenetic modifiers of tau pathologies lead to heterogeneous clinicopathological features. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

DOI： 10.1002/mds.27623

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11C-PBB3 PETによる皮質基底核症候群におけるタウ病変と神経障害の連関の検討

島田斉, 佐原成彦, 須原哲也, 樋口真人, 桑原聡, 仲野義和, 平野成樹, 篠遠仁

千葉医学雑誌 95 ( 2 ) 57 - 57 2019.4

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Tau imaging detects distinctive distribution of tau pathology in ALS/PDC on the Kii Peninsula. Reviewed International journal

Hitoshi Shinotoh, Hitoshi Shimada, Yasumasa Kokubo, Kenji Tagai, Fumitoshi Niwa, Soichiro Kitamura, Hironobu Endo, Maiko Ono, Yasuyuki Kimura, Shigeki Hirano, Maya Mimuro, Masanori Ichise, Naruhiko Sahara, Ming-Rong Zhang, Tetsuya Suhara, Makoto Higuchi

Neurology 92 ( 2 ) e136-e147 - e147 2019.1

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OBJECTIVE: To characterize the distribution of tau pathology in patients with amyotrophic lateral sclerosis/parkinsonism dementia complex on the Kii Peninsula (Kii ALS/PDC) by tau PET using [11C]PBB3 as ligand. METHODS: This is a cross-sectional study of 5 patients with ALS/PDC and one asymptomatic participant with a dense family history of ALS/PDC from the Kii Peninsula who took part in this study. All were men, and their age was 76 ± 8 (mean ± SD) years. Thirteen healthy men (69 ± 6 years) participated as healthy controls (HCs). Dynamic PET scans were performed following injection of [11C]PBB3, and parametric PET images were generated by voxel-by-voxel calculation of binding potential (BP*ND) using a multilinear reference tissue model. [11C] Pittsburgh compound B (PiB) PET, MRI, and cognitive tests were also performed. RESULTS: A voxel-based comparison of [11C]PBB3 BP*ND illustrated PET-detectable tau deposition in the cerebral cortex and white matter, and pontine basis including the corticospinal tract in Kii ALS/PDC patients compared with HCs (uncorrected p < 0.05). Group-wise volume of interest analysis of [11C]PBB3 BP*ND images showed increased BP*ND in the hippocampus and in frontal and parietal white matters of Kii ALS/PDC patients relative to HCs (p < 0.05, Holm-Sidak multiple comparisons test). BP*ND in frontal, temporal, and parietal gray matters correlated with Mini-Mental State Examination scores in Kii ALS/PDC patients (p < 0.05). All Kii ALS/PDC patients were negative for [11C]PiB (β-amyloid) except one with marginal positivity. CONCLUSION: [11C]PBB3 PET visualized the characteristic topography of tau pathology in Kii ALS/PDC, corresponding to clinical phenotypes of this disease.

DOI： 10.1212/WNL.0000000000006736

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タウオパチーモデルマウスにおける脳代謝産物とtauタンパク質蓄積の相関(Correlations between brain metabolites and tau protein accumulation in a tauopathy mouse model)

高堂裕平, 田桑弘之, 漆畑拓弥, 高橋真奈美, 小野麻衣子, 前田純, 下條雅文, 新田展大, 柴田さやか, 青木伊知男, 佐原成彦, 須原哲也, 樋口真人

臨床神経学 58 ( Suppl. ) S275 - S275 2018.12

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mGluR5受容体PETを指標としたrTg4510マウスモデル脳における神経機能病態の画像診断

下條雅文, 徳永正希, 田桑弘之, 高堂裕平, 前田純, 漆畑拓也, 南久松丈晴, 張明栄, 青木伊知男, 須原哲也, 佐原成彦, 樋口真人

Dementia Japan 32 ( 3 ) 439 - 439 2018.9

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認知症の増悪に関わる脳アミロイドアンギオパチーモデル動物を用いた治療標的探索

北爪しのぶ, 今牧理恵, 立田由里子, 木塚康彦, 斎藤貴志, 西道隆臣, 佐原成彦, 冨本秀和, 谷口直之

Dementia Japan 32 ( 3 ) 426 - 426 2018.9

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タウオパチーマウスにおいてタウタンパク質は神経障害を誘発したタウPETとH-MRSによる研究(Tau protein induced neural impairment in tauopathy mice: tau PET and H-MRS study)

高堂裕平, 田桑弘之, 漆畑拓弥, 高橋真奈美, 小野麻衣子, 前田純, 下條雅文, 新田展大, 柴田さやか, 青木伊知男, 佐原成彦, 須原哲也, 樋口真人

Dementia Japan 32 ( 3 ) 439 - 439 2018.9

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Comparative In Vitro and In Vivo Quantifications of Pathologic Tau Deposits and Their Association with Neurodegeneration in Tauopathy Mouse Models. Reviewed International journal

Ruiqing Ni, Bin Ji, Maiko Ono, Naruhiko Sahara, Ming-Rong Zhang, Ichio Aoki, Agneta Nordberg, Tetsuya Suhara, Makoto Higuchi

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 59 ( 6 ) 960 - 966 2018.6

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Fibrillary tau aggregates in Alzheimer disease and allied neurodegenerative disorders have been visualized in vivo by PET, whereas mechanistic links between PET-detectable tau deposits and neurotoxicity remain elusive. Here, we took advantage of transgenic mouse models of tauopathies to evaluate associations between PET and postmortem measures of tau probe binding and their relation to neuronal loss. Methods: PET with a tau probe, 11C-PBB3 (2-((1E,3E)-4-(6-(11C-methylamino)pyridine-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol), and volumetric MRI were performed for transgenic rTg4510 mice and nontransgenic mice. Binding of 11C-PBB3 and its blockade by another tau binding compound, AV-1451 (-(6-fluoropyridine-3-yl)-5H-pyrido[4,3-b]indole), in homogenized brains of tauopathy patients and rTg4510 and PS19 mice were quantified, and 11C-PBB3-positive and phosphorylated tau lesions in sectioned brains of these mice were assessed. Results: In vivo 11C-PBB3 binding to the rTg4510 neocortex/hippocampus was increased relative to controls and correlated with local atrophy. In vitro 11C-PBB3 binding in the neocortex/hippocampus also correlated well with in vivo radioligand binding and regional atrophy in the same individual rTg4510 mice. By contrast, in vitro 11C-PBB3 binding was elevated in the brain stem but not hippocampus of PS19 mice, despite a pronounced loss of neurons in the hippocampus rather than brain stem. Finally, 11C-PBB3 and AV-1451 showed similar binding properties between mouse models and tauopathy patients. Conclusion: The present findings support the distinct utilities of 11C-PBB3 PET and MRI in rTg4510 and PS19 mice for quantitatively pursuing mechanisms connecting PET-detectable and PET-undetectable tau aggregations to neuronal death, which recapitulate 2 different modes of tau-provoked neurotoxicity.

DOI： 10.2967/jnumed.117.201632

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Tau Fibril Formation in Cultured Cells Compatible with a Mouse Model of Tauopathy. Reviewed International journal

Gen Matsumoto, Kazuki Matsumoto, Taeko Kimura, Tetsuya Suhara, Makoto Higuchi, Naruhiko Sahara, Nozomu Mori

International journal of molecular sciences 19 ( 5 ) 2018.5

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DOI： 10.3390/ijms19051497

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Biochemical Properties of Pathology-Related Tau Species in Tauopathy Brains: An Extraction Protocol for Tau Oligomers and Aggregates. Reviewed International journal

Naruhiko Sahara, Taeko Kimura

Methods in molecular biology (Clifton, N.J.) 1779 435 - 445 2018

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Language：English Publishing type：Research paper (scientific journal) Publisher：Humana Press Inc.

DOI： 10.1007/978-1-4939-7816-8_26

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In Vivo Visualization of Tau Accumulation, Microglial Activation, and Brain Atrophy in a Mouse Model of Tauopathy rTg4510. Reviewed International journal

Ai Ishikawa, Masaki Tokunaga, Jun Maeda, Takeharu Minamihisamatsu, Masafumi Shimojo, Hiroyuki Takuwa, Maiko Ono, Ruiqing Ni, Shigeki Hirano, Satoshi Kuwabara, Bin Ji, Ming-Rong Zhang, Ichio Aoki, Tetsuya Suhara, Makoto Higuchi, Naruhiko Sahara

Journal of Alzheimer's disease : JAD 61 ( 3 ) 1037 - 1052 2018

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BACKGROUND: Tau imaging using PET is a promising tool for the diagnosis and evaluation of tau-related neurodegenerative disorders, but the relationship among PET-detectable tau, neuroinflammation, and neurodegeneration is not yet fully understood. OBJECTIVE: We aimed to elucidate sequential changes in tau accumulation, neuroinflammation, and brain atrophy by PET and MRI in a tauopathy mouse model. METHODS: rTg4510 transgenic (tg) mice expressing P301L mutated tau and non-tg mice were examined with brain MRI and PET imaging (analyzed numbers: tg = 17, non-tg = 13; age 2.5∼14 months). As PET probes, [11C]PBB3 (Pyridinyl-Butadienyl-Benzothiazole 3) and [11C]AC-5216 were used to visualize tau pathology and 18-kDa translocator protein (TSPO) neuroinflammation. Tau pathology and microglia activation were subsequently analyzed by histochemistry. RESULTS: PET studies revealed age-dependent increases in [11C]PBB3 and [11C]AC-5216 signals, which were correlated with age-dependent volume reduction in the forebrain on MRI. However, the increase in [11C]PBB3 signals reached a plateau at age 7 months, and therefore its significant correlation with [11C]AC-5216 disappeared after age 7 months. In contrast, [11C]AC-5216 showed a strong correlation with both age and volume reduction until age 14 months. Histochemical analyses confirmed the relevance of pathological tau accumulation and elevated TSPO immunoreactivity in putative microglia. CONCLUSION: Our results showed that tau accumulation is associated with neuroinflammation and brain atrophy in a tauopathy mouse model. The time-course of the [11C]PBB3- and TSPO-PET finding suggests that tau deposition triggers progressive neuroinflammation, and the sequential changes can be evaluated in vivo in mouse brains.

DOI： 10.3233/JAD-170509

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Tau Filaments and the Development of Positron Emission Tomography Tracers. Reviewed International journal

Michel Goedert, Yoshiki Yamaguchi, Sushil K Mishra, Makoto Higuchi, Naruhiko Sahara

Frontiers in neurology 9 70 - 70 2018

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Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers Media S.A.

DOI： 10.3389/fneur.2018.00070

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Microglial Activation During Pathogenesis of Tauopathy in rTg4510 Mice: Implications for the Early Diagnosis of Tauopathy. Reviewed International journal

Naruhiko Sahara, Jun Maeda, Ai Ishikawa, Masaki Tokunaga, Tetsuya Suhara, Makoto Higuchi

Journal of Alzheimer's disease : JAD 64 ( s1 ) S353-S359 - S359 2018

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Language：English Publishing type：Research paper (scientific journal) Publisher：IOS Press

DOI： 10.3233/JAD-179933

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[Development of imaging-based diagnostic procedures for brain protein aging using a mouse model of tauopathy]. Reviewed

Sahara N

Nihon yakurigaku zasshi. Folia pharmacologica Japonica 152 ( 1 ) 4 - 9 2018

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Language：Japanese Publishing type：Research paper (scientific journal)

An increasing age is the greatest risk factor for dementia and related disorders. Therefore, much attention has been focus on researches to understand mechanisms of disease-related brain aging. Neurodegenerative diseases including Alzheimer's disease (AD), dementia with lewy bodies, and frontotemporal lobar degeneration are mostly diagnosed by neuropathological features with protein inclusions such as Aβ, tau, α-synuclein, TDP-43, and FUS. These proteins are expected to lose physiological functions and mutual interaction with functional molecule with aging. Consecutively, acquired pathogenicities of aged proteins are accumulated and propagated in neural cells. The research for "Brain protein aging" is developed for understanding the mechanisms of initiation and pathogenicity of aging. Tau protein is one of major components of neurofibrillary tangles, which are closely associated with the severity of brain function loss of AD. To investigate tau protein's Brain protein aging, we have currently developed the in vivo multimodal imaging techniques for visualizing the progression of tau pathology. In this review, we will introduce such a novel imaging-based diagnostic procedures on a mouse model of tauopathy.

DOI： 10.1254/fpj.152.4

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In Vivo Tau imaging for a Diagnostic Platform of Tauopathy Using the rTg4510 Mouse Line Reviewed International journal

Naruhiko Sahara, Masafumi Shimojo, Maiko Ono, Hiroyuki Takuwa, Marcelo Febo, Makoto Higuchi, Tetsuya Suhara

FRONTIERS IN NEUROLOGY 8 663 - 663 2017.12

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DOI： 10.3389/fneur.2017.00663

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新規タウPETトレーサー[18F]AM-PBB3と[18F]PM-PBB3の開発

小野麻衣子, 北村聡一郎, 島田斉, 佐原成彦, 田桑弘之, 吉山容正, Trojanowski John Q., Lee Virginia M.-Y., 須原哲也, 張明栄, Jang Ming-Kuei, 樋口真人

Dementia Japan 31 ( 4 ) 577 - 577 2017.10

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脳アミロイドアンギオパチーを示す新規モデルマウスの開発

北爪しのぶ, 今牧理恵, 立田由里子, 木塚康彦, 佐原成彦, 冨本秀和, 斉藤貴志, 西道隆臣, 谷口直之

Dementia Japan 31 ( 4 ) 565 - 565 2017.10

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同一トレーサーでつなぐモデルマウスタウ病態のPET インビボ蛍光画像解析

田桑弘之, 石川愛, 高堂裕平, 下條雅文, 小野麻衣子, 漆畑拓弥, 高橋真奈美, 佐原成彦, 須原哲也, 樋口真人

Dementia Japan 31 ( 4 ) 569 - 569 2017.10

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Fluorescence and Autoradiographic Evaluation of Tau PET Ligand PBB3 to alpha-Synuclein Pathology Reviewed International journal

Shunsuke Koga, Maiko Ono, Naruhiko Sahara, Makoto Higuchi, Dennis W. Dickson

MOVEMENT DISORDERS 32 ( 6 ) 884 - 892 2017.6

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DOI： 10.1002/mds.27013

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Delayed-Onset Psychosis following TBI is Associated with Tau Depositions in the Neocortex but Not with beta-Amyloid Depositions: A Pet Study with [11C] PBB3 and [11C]PiB Reviewed

Takahata Keisuke, Kimura Yasuyuki, Shimada Hitoshi, Ichise Masanori, Tabuchi Hajime, Kitamura Soichiro, Kubota Manabu, Moriguchi Sho, Ishii Tatsuya, Nina Fumitoshi, d Hironobu, Morimoto Yoko, Funayama Michitaka, Onaya Matsumoto, Sahara Naruhiko, Umeda Satoshi, Mimura Masaru, Higuchi Makoto, Suhara Tetsuya

BIOLOGICAL PSYCHIATRY 81 ( 10 ) S295 - S296 2017.5

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Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies Reviewed International journal

Maiko Ono, Naruhiko Sahara, Katsushi Kumata, Bin Ji, Ruiqing Ni, Shunsuke Koga, Dennis W. Dickson, John Q. Trojanowski, Virginia M-Y. Lee, Mari Yoshida, Isao Hozumi, Yasumasa Yoshiyama, John C. van Swieten, Agneta Nordberg, Tetsuya Suhara, Ming-Rong Zhang, Makoto Higuchi

BRAIN 140 ( 3 ) 764 - 780 2017.3

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DOI： 10.1093/brain/aww339

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Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes Reviewed International journal

Shinsuke Ishigaki, Yusuke Fujioka, Yohei Okada, Yuichi Riku, Tsuyoshi Udagawa, Daiyu Honda, Satoshi Yokoi, Kuniyuki Endo, Kensuke Ikenaka, Shinnosuke Takagi, Yohei Iguchi, Naruhiko Sahara, Akihiko Takashima, Hideyuki Okano, Mari Yoshida, Hitoshi Warita, Masashi Aoki, Hirohisa Watanabe, Haruo Okado, Masahisa Katsuno, Gen Sobue

CELL REPORTS 18 ( 5 ) 1118 - 1131 2017.1

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DOI： 10.1016/j.celrep.2017.01.013

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Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons Reviewed International journal

Keiko Imamura, Naruhiko Sahara, Nicholas M. Kanaan, Kayoko Tsukita, Takayuki Kondo, Yumiko Kutoku, Yutaka Ohsawa, Yoshihide Sunada, Koichi Kawakami, Akitsu Hotta, Satoshi Yawata, Dai Watanabe, Masato Hasegawa, John Q. Trojanowski, Virginia M. -Y. Lee, Tetsuya Suhara, Makoto Higuchi, Haruhisa Inoue

SCIENTIFIC REPORTS 6 34904 - 34904 2016.10

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DOI： 10.1038/srep34904

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健康長寿社会をめざして核医学の挑戦認知症の克服に向けた核医学の貢献

樋口真人, 島田斉, 木村泰之, 佐原成彦, 堀口隆司, 須原哲也

核医学 53 ( Suppl. ) S54 - S54 2016.10

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神経変性疾患の最前線2016 変性型認知症の分子イメージング(Molecular imaging of neurodegenerative dementias)

樋口真人, 島田斉, 田桑弘之, 佐原成彦, 須原哲也

日本神経精神薬理学会年会プログラム・抄録集 46回 84 - 84 2016.7

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PET Quantification of Tau Pathology in Human Brain with C-11-PBB3 Reviewed International journal

Yasuyuki Kimura, Masanori Ichise, Hiroshi Ito, Hitoshi Shimada, Yoko Ikoma, Chie Seki, Harumasa Takano, Soichiro Kitamura, Hitoshi Shinotoh, Kazunori Kawamura, Ming-Rong Zhang, Naruhiko Sahara, Tetsuya Suhara, Makoto Higuchi

JOURNAL OF NUCLEAR MEDICINE 56 ( 9 ) 1359 - 1365 2015.9

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DOI： 10.2967/jnumed.115.160127

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Imaging Multimodalities for Dissecting Alzheimer's Disease: Advanced Technologies of Positron Emission Tomography and Fluorescence Imaging. Reviewed International journal

Masafumi Shimojo, Makoto Higuchi, Tetsuya Suhara, Naruhiko Sahara

Frontiers in neuroscience 9 482 - 482 2015

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The rapid progress in advanced imaging technologies has expanded our toolbox for monitoring a variety of biological aspects in living subjects including human. In vivo radiological imaging using small chemical tracers, such as with positron emission tomography, represents an especially vital breakthrough in the efforts to improve our understanding of the complicated cascade of neurodegenerative disorders including Alzheimer's disease (AD), and it has provided the most reliable visible biomarkers for enabling clinical diagnosis. At the same time, in combination with genetically modified animal model systems, the most recent innovation of fluorescence imaging is helping establish diverse applications in basic neuroscience research, from single-molecule analysis to animal behavior manipulation, suggesting the potential utility of fluorescence technology for dissecting the detailed molecular-based consequence of AD pathophysiology. In this review, our primary focus is on a current update of PET radiotracers and fluorescence indicators beneficial for understanding the AD cascade, and discussion of the utility and pitfalls of those imaging modalities for future translational research applications. We will also highlight current cutting-edge genetic approaches and discuss how to integrate individual technologies for further potential innovations.

DOI： 10.3389/fnins.2015.00482

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TOC1: A valuable tool in assessing disease progression in the rTg4510 mouse model of tauopathy Reviewed International journal

Sarah M. Ward, Diana S. Himmelstein, Yan Ren, Yifan Fu, Xiao-Wen Yu, Kaleigh Roberts, Lester I. Binder, Naruhiko Sahara

NEUROBIOLOGY OF DISEASE 67 37 - 48 2014.7

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DOI： 10.1016/j.nbd.2014.03.002

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Age-related decline in white matter integrity in a mouse model of tauopathy: an in vivo diffusion tensor magnetic resonance imaging study Reviewed International journal

Naruhiko Sahara, Pablo D. Perez, Wen-Lang Lin, Dennis W. Dickson, Yan Ren, Huadong Zeng, Jada Lewis, Marcelo Febo

NEUROBIOLOGY OF AGING 35 ( 6 ) 1364 - 1374 2014.6

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DOI： 10.1016/j.neurobiolaging.2013.12.009

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Effects of the C57BL/6 strain background on tauopathy progression in the rTg4510 mouse model Reviewed International journal

Rachel M. Bailey, John Howard, Joshua Knight, Naruhiko Sahara, Dennis W. Dickson, Jada Lewis

MOLECULAR NEURODEGENERATION 9 8 - 8 2014.1

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DOI： 10.1186/1750-1326-9-8

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Endogenous Tau Aggregates in Oligodendrocytes of rTg4510 Mice Induced by Human P301L Tau Reviewed International journal

Yan Ren, Wen-Lang Lin, Laura Sanchez, Carolina Ceballos, Manuela Polydoro, Tara L. Spires-Jones, Bradley T. Hyman, Dennis W. Dickson, Naruhiko Sahara

JOURNAL OF ALZHEIMERS DISEASE 38 ( 3 ) 589 - 600 2014

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DOI： 10.3233/JAD-130986

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Tau Oligomers as Potential Targets for Early Diagnosis of Tauopathy Reviewed International journal

Naruhiko Sahara, Yan Ren, Sarah Ward, Lester I. Binder, Tetsuya Suhara, Makoto Higuchi

JOURNAL OF ALZHEIMERS DISEASE 40 S91 - S96 2014

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DOI： 10.3233/JAD-132429

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Biochemical distribution of tau protein in synaptosomal fraction of transgenic mice expressing human P301L tau Reviewed International journal

Naruhiko Sahara, Miyuki Murayama, Makoto Higuchi, Tetsuya Suhara, Akihiko Takashima

FRONTIERS IN NEUROLOGY 5 26 - 26 2014

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DOI： 10.3389/fneur.2014.00026

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"Tau oligomers," what we know and what we don't know Reviewed International journal

Naruhiko Sahara, Jesus Avila

FRONTIERS IN NEUROLOGY 5 1 - 1 2014

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DOI： 10.3389/fneur.2014.00001

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Tau PET Imaging of Neurocognitive Disorders Using Newly Developed Tau Ligand [11C]PBB3 Reviewed

Suhara Tetsuya, Shimada Hitoshi, Maruyama Masahiro, Shinotoh Hitoshi, Ji Bin, Maeda Jun, Takano Harumasa, Sahara Naruhiko, Zhang Ming-Rong, Ito Hiroshi, Higuchi Makoto

NEUROPSYCHOPHARMACOLOGY 38 S159 - S160 2013.12

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Imaging of Tau Pathology in a Tauopathy Mouse Model and in Alzheimer Patients Compared to Normal Controls Reviewed International journal

Masahiro Maruyama, Hitoshi Shimada, Tetsuya Suhara, Hitoshi Shinotoh, Bin Ji, Jun Maeda, Ming-Rong Zhang, John Q. Trojanowski, Virginia M. -Y. Lee, Maiko Ono, Kazuto Masamoto, Harumasa Takano, Naruhiko Sahara, Nobuhisa Iwata, Nobuyuki Okamura, Shozo Furumoto, Yukitsuka Kudo, Qing Chang, Takaomi C. Saido, Akihiko Takashima, Jada Lewis, Ming-Kuei Jang, Ichio Aoki, Hiroshi Ito, Makoto Higuchi

NEURON 79 ( 6 ) 1094 - 1108 2013.9

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DOI： 10.1016/j.neuron.2013.07.037

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Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy Reviewed International journal

Amy K. Clippinger, Simon D'Alton, Wen-Lang Lin, Tania F. Gendron, John Howard, David R. Borchelt, Ashley Cannon, Yari Carlomagno, Paramita Chakrabarty, Casey Cook, Todd E. Golde, Yona Levites, Laura Ranum, Patrick J. Schultheis, Guilian Xu, Leonard Petrucelli, Naruhiko Sahara, Dennis W. Dickson, Benoit Giasson, Jada Lewis

ACTA NEUROPATHOLOGICA 126 ( 1 ) 39 - 50 2013.7

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DOI： 10.1007/s00401-013-1123-8

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In vivo functional brain mapping in a conditional mouse model of human tauopathy (tau(p301l)) reveals reduced neural activity in memory formation structures Reviewed International journal

Pablo D. Perez, Gabrielle Hall, Tetsuya Kimura, Yan Ren, Rachel M. Bailey, Jada Lewis, Marcelo Febo, Naruhiko Sahara

MOLECULAR NEURODEGENERATION 8 9 - 9 2013.2

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DOI： 10.1186/1750-1326-8-9

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Characteristics of tau oligomers. Reviewed International journal

Ren Y, Sahara N

Frontiers in neurology 4 102 - 102 2013

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In Alzheimer disease (AD) and other tauopathies, microtubule-associated protein tau becomes hyperphosphorylated, undergoes conformational changes, aggregates, eventually becoming neurofibrillary tangles (NFTs). As accumulating evidence suggests that NFTs themselves may not be toxic, attention is now turning toward the role of intermediate tau oligomers in AD pathophysiology. Sarkosyl extraction is a standard protocol for investigating insoluble tau aggregates in brains. There is a growing consensus that sarkosyl-insoluble tau correlates with the pathological features of tauopathy. While sarkosyl-insoluble tau from tauopathy brains has been well characterized as a pool of filamentous tau, other dimers, multimers, and granules of tau are much less well understood. There are protocols for identifying these tau oligomers. In this mini review, we discuss the characteristics of tau oligomers isolated via different methods and materials.

DOI： 10.3389/fneur.2013.00102

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Characteristics of TBS-Extractable Hyperphosphorylated Tau Species: Aggregation Intermediates in rTg4510 Mouse Brain Reviewed International journal

Naruhiko Sahara, Michael DeTure, Yan Ren, Abdul-Shukkur Ebrahim, Dongcheul Kang, Joshua Knight, Christiane Volbracht, Jan Torleif Pedersen, Dennis W. Dickson, Shu-Hui Yen, Jada Lewis

JOURNAL OF ALZHEIMERS DISEASE 33 ( 1 ) 249 - 263 2013

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DOI： 10.3233/JAD-2012-121093

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Adaptive responses to alloxan-induced mild oxidative stress ameliorate certain tauopathy phenotypes Reviewed International journal

Yuji Yoshiike, Shunji Yamashita, Tatsuya Mizoroki, Sumihiro Maeda, Miyuki Murayama, Tetsuya Kimura, Naruhiko Sahara, Yoshiyuki Soeda, Akihiko Takashima

AGING CELL 11 ( 1 ) 51 - 62 2012.2

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DOI： 10.1111/j.1474-9726.2011.00756.x

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Propagation of Tau Pathology in a Model of Early Alzheimer's Disease Reviewed International journal

Alix de Calignon, Manuela Polydoro, Marc Suarez-Calvet, Christopher William, David H. Adamowicz, Kathy J. Kopeikina, Rose Pitstick, Naruhiko Sahara, Karen H. Ashe, George A. Carlson, Tara L. Spires-Jones, Bradley T. Hyman

NEURON 73 ( 4 ) 685 - 697 2012.2

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DOI： 10.1016/j.neuron.2011.11.033

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Immunoelectron Microscopic and Biochemical Studies of Caspase-Cleaved Tau in a Mouse Model of Tauopathy Reviewed International journal

Wen-Lang Lin, Dennis W. Dickson, Naruhiko Sahara

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 70 ( 9 ) 779 - 787 2011.9

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DOI： 10.1097/NEN.0b013e31822ac9c9

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Differential regional distribution of phosphorylated tau and synapse loss in the nucleus accumbens in tauopathy model mice Reviewed International journal

Taiki Kambe, Yumiko Motoi, Ran Inoue, Nobuhiko Kojima, Norihiro Tada, Tetsuya Kimura, Naruhiko Sahara, Shunji Yamashita, Tatsuya Mizoroki, Akihiko Takashima, Kohei Shimada, Koichi Ishiguro, Hiroshi Mizuma, Hirotaka Onoe, Yoshikuni Mizuno, Nobutaka Hattori

NEUROBIOLOGY OF DISEASE 42 ( 3 ) 404 - 414 2011.6

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DOI： 10.1016/j.nbd.2011.02.002

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Aggregation of Detergent-insoluble Tau Is Involved in Neuronal Loss but Not in Synaptic Loss Reviewed International journal

Tetsuya Kimura, Tetsuya Fukuda, Naruhiko Sahara, Shunji Yamashita, Miyuki Murayama, Tatsuya Mizoroki, Yuji Yoshiike, Boyoung Lee, Ioannis Sotiropoulos, Sumihiro Maeda, Akihiko Takashima

JOURNAL OF BIOLOGICAL CHEMISTRY 285 ( 49 ) 38692 - 38699 2010.12

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DOI： 10.1074/jbc.M110.136630

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Tau and neurodegenerative disorders Reviewed International journal

Yumiko Motoi, Naruhiko Sahara, Taiki Kambe, Nobutaka Hattori

Biomolecular Concepts 1 ( 2 ) 131 - 145 2010.8

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DOI： 10.1515/bmc.2010.017

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Comprehensive and innovative techniques for liver transplantation in rats: A surgical guide Reviewed International journal

Tomohide Hori, Justin H. Nguyen, Xiangdong Zhao, Yasuhiro Ogura, Toshiyuki Hata, Shintaro Yagi, Feng Chen, Ann-Marie T. Baine, Norifumi Ohashi, Christopher B. Eckman, Aimee R. Herdt, Hiroto Egawa, Yasutsugu Takada, Fumitaka Oike, Seisuke Sakamoto, Mureo Kasahara, Kohei Ogawa, Koichiro Hata, Taku Iida, Yukihide Yonekawa, Lena Sibulesky, Kagemasa Kuribayashi, Takuma Kato, Kanako Saito, Linan Wang, Mie Torii, Naruhiko Sahara, Naoko Kamo, Tomoko Sahara, Motohiko Yasutomi, Shinji Uemoto

WORLD JOURNAL OF GASTROENTEROLOGY 16 ( 25 ) 3120 - 3132 2010.7

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DOI： 10.3748/wjg.v16.i25.3120

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Promotion of CHIP-Mediated p53 Degradation Protects the Heart From Ischemic Injury Reviewed International journal

Atsuhiko T. Naito, Sho Okada, Tohru Minamino, Koji Iwanaga, Mei-Lan Liu, Tomokazu Sumida, Seitaro Nomura, Naruhiko Sahara, Tatsuya Mizoroki, Akihiko Takashima, Hiroshi Akazawa, Toshio Nagai, Ichiro Shiojima, Issei Komuro

CIRCULATION RESEARCH 106 ( 11 ) 1692 - U69 2010.6

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DOI： 10.1161/CIRCRESAHA.109.214346

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Amyloid precursor protein and tau transgenic models of Alzheimer's disease: insights from the past and directions for the future. Reviewed International journal

Sahara N, Lewis J

Future neurology 5 ( 3 ) 411 - 420 2010.5

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During the last 20 years, our understanding of the mechanisms underlying Alzheimer's disease (AD) has considerably improved, in part owing to both in vitro and in vivo model systems. Studies in mice expressing both human amyloid precursor protein and human tau have provided clear evidence that amyloid-beta and tau interact in the pathogenesis of AD. Moreover, amyloid-beta toxicity has been shown to be tau-dependent since reducing tau levels prevents behavioral deficits and sudden death in amyloid precursor protein transgenic mice. As tau pathology preferentially develops in specific sites and spreads in a predictable manner across the brain, understanding the mechanism underlying tau dysfunction should be a focus in AD mouse modeling. A defined effort must be made to develop therapies that directly address the impact of tau dysfunction in the pathogenesis of AD. Finally, early diagnosis of AD is essential and this must be made possible by identification of early biomarkers, behavioral changes or use of novel imaging techniques.

DOI： 10.2217/fnl.10.10

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Tau Oligomerization: A Role for Tau Aggregation Intermediates Linked to Neurodegeneration Invited Reviewed

N. Sahara, S. Maeda, A. Takashima

CURRENT ALZHEIMER RESEARCH 5 ( 6 ) 591 - 598 2008.12

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DOI： 10.2174/156720508786898442

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GSK-3 beta Is Required for Memory Reconsolidation in Adult Brain Reviewed International journal

Tetsuya Kimura, Shunji Yamashita, Shinobu Nakao, Jung-Mi Park, Miyuki Murayama, Tatsuya Mizoroki, Yuji Yoshiike, Naruhiko Sahara, Akihiko Takashima

PLOS ONE 3 ( 10 ) e3540 2008.10

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DOI： 10.1371/journal.pone.0003540

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Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in cell models and knock-in mouse brains - Familial Alzheimer disease-linked mutation impairs gamma-site cleavage of amyloid precursor protein C-terminal fragment beta Reviewed International journal

Masafumi Shimojo, Naruhiko Sahara, Tatsuya Mizoroki, Satoru Funamoto, Maho Morishima-Kawashima, Takashi Kudo, Masatoshi Takeda, Yasuo Ihara, Hiroshi Ichinose, Akihiko Takashima

JOURNAL OF BIOLOGICAL CHEMISTRY 283 ( 24 ) 16488 - 16496 2008.6

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DOI： 10.1074/jbc.M801279200

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Active c-jun N-terminal kinase induces caspase cleavage of tau and additional phosphorylation by GSK-3 beta is required for tau aggregation Reviewed International journal

Naruhiko Sahara, Miyuki Murayama, Boyoung Lee, Jung-Mi Park, Sarita Lagalwar, Lester I. Binder, Akihiko Takashima

EUROPEAN JOURNAL OF NEUROSCIENCE 27 ( 11 ) 2897 - 2906 2008.6

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DOI： 10.1111/j.1460-9568.2008.06258.x

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Hyperphosphorylated tau in parahippocampal cortex impairs place learning in aged mice expressing wild-type human tau Reviewed International journal

Tetsuya Kimura, Shunji Yamashita, Tetsuya Fukuda, Jun-Mi Park, Miyuki Murayama, Tatsuya Mizoroki, Yuji Yoshiike, Naruhiko Sahara, Akihiko Takashima

EMBO JOURNAL 26 ( 24 ) 5143 - 5152 2007.12

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DOI： 10.1038/sj.emboj.7601917

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Molecular chaperone-mediated Tau protein metabolism counteracts the formation of granular Tau oligomers in human brain Reviewed

N. Sahara, S. Maeda, Y. Yoshiike, T. Mizoroki, S. Yamashita, M. Murayama, J. -M. Park, Y. Saito, S. Murayama, A. Takashima

JOURNAL OF NEUROSCIENCE RESEARCH 85 ( 14 ) 3098 - 3108 2007.11

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DOI： 10.1002/jnr.21417

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Aluminum induces tau aggregation in vitro but not in vivo Reviewed International journal

Tatsuya Mizoroki, Shunsuke Meshitsuka, Sumihiro Maeda, Miyuki Murayama, Naruhiko Sahara, Akihiko Takashima

JOURNAL OF ALZHEIMERS DISEASE 11 ( 4 ) 419 - 427 2007.7

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Novel conformation-sensitive antibodies specific to three- and four-repeat tau Reviewed International journal

Hitomi Ueno, Ohoshi Murayama, Sumihiro Maeda, Naruhiko Sahara, Jung-Mi Park, Mlyuki Murayama, Akihiro Sanda, Kazuhiko Iwahashi, Motoo Matsuda, Akihiko Takashima

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 358 ( 2 ) 602 - 607 2007.6

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DOI： 10.1016/j.bbrc.2007.04.176

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Assembly of two distinct dimers and higher-order oligomers from full-length tau Reviewed International journal

Naruhiko Sahara, Sumihiro Maeda, Miyuki Murayama, Takehiro Suzuki, Naoshi Dohmae, Shu-Hui Yen, Akihiko Takashima

EUROPEAN JOURNAL OF NEUROSCIENCE 25 ( 10 ) 3020 - 3029 2007.5

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DOI： 10.1111/j.1460-9568.2007.05555.x

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Granular tau oligomers as intermediates of tau filaments Reviewed International journal

Sumihiro Maeda, Naruhiko Sahara, Yuko Saito, Miyuki Murayama, Yuji Yoshiike, Hyonchol Kim, Tomohiro Miyasaka, Shigeo Murayama, Atsushi Ikai, Akihiko Takashima

BIOCHEMISTRY 46 ( 12 ) 3856 - 3861 2007.3

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DOI： 10.1021/bi061359o

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Decreased A beta secretion by cells expressing familial Alzheimer's disease-linked mutant presenilin 1 Reviewed International journal

Masafumi Shimojo, Naruhiko Sahara, Miyuki Murayama, Hiroshi Ichinose, Akihiko Takashima

NEUROSCIENCE RESEARCH 57 ( 3 ) 446 - 453 2007.3

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DOI： 10.1016/j.neures.2006.12.005

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Increased levels of granular tau oligomers: An early sign of brain aging and Alzheimer's disease Reviewed International journal

S Maeda, N Sahara, Y Saito, S Murayama, A Ikai, A Takashima

NEUROSCIENCE RESEARCH 54 ( 3 ) 197 - 201 2006.3

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DOI： 10.1016/j.neures.2005.11.009

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c-jun N-terminal kinase hyperphosphorylates R406W tau at the PHF-1 site during mitosis Reviewed International journal

Yoshitaka Tatebayashi, Emmanuel Planel, De-Hua Chui, Shinji Sato, Tomohiro Miyasaka, Naruhiko Sahara, Miyuki Murayama, Naomi Kikuchi, Katsuji Yoshioka, Ravid Rivka, Akihiko Takashima

FASEB JOURNAL 20 ( 2 ) 762 - + 2006.2

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DOI： 10.1096/fj.05-4362fje

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In vivo evidence of CHIP up-regulation attenuating tau aggregation Reviewed International journal

N Sahara, M Murayama, T Mizoroki, M Urushitani, Y Imai, R Takahashi, S Murata, K Tanaka, A Takashima

JOURNAL OF NEUROCHEMISTRY 94 ( 5 ) 1254 - 1263 2005.9

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DOI： 10.1111/j.1471-4159.2005.03272.x

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Recent advances in experimental modeling of the assembly of tau filaments. Reviewed International journal

Ko LW, DeTure M, Sahara N, Chihab R, Vega IE, Yen SH

Biochimica et biophysica acta 1739 ( 2-3 ) 125 - 139 2005.1

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Intracellular assembly of microtubule-associated protein tau into filamentous inclusions is central to Alzheimer's disease and related disorders collectively known as tauopathies. Although tau mutations, posttranslational modifications and degradations have been the focus of investigations, the mechanism of tau fibrillogenesis in vivo still remains elusive. Different strategies have been undertaken to generate animal and cellular models for tauopathies. Some are used to study the molecular events leading to the assembly and accumulation of tau filaments, and others to identify potential therapeutic agents that are capable of impeding tauopathy. This review highlights the latest developments in new models and how their utility improves our understanding of the sequence of events leading to human tauopathy.

DOI： 10.1016/j.bbadis.2004.09.004

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Assembly of filamentous tau aggregates in human neuronal cells Reviewed International journal

LW Ko, T Rush, N Sahara, JS Kersh, C Easson, M DeTure, WL Lin, YD Connor, SHC Yen

JOURNAL OF ALZHEIMERS DISEASE 6 ( 6 ) 605 - 622 2004.12

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Phosphorylated p38MAPK specific antibodies cross-react with sarkosyl-insoluble hyperphosphorylated tau proteins Reviewed International journal

N Sahara, IE Vega, T Ishizawa, J Lewis, E McGowan, M Hutton, D Dickson, SH Yen

JOURNAL OF NEUROCHEMISTRY 90 ( 4 ) 829 - 838 2004.8

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DOI： 10.1111/j.1471-4159.2004.02558.x

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A novel tau mutation in exon 9 (1260V) causes a four-repeat tauopathy Reviewed International journal

A Grover, E England, M Baker, N Sahara, J Adamson, B Granger, H Houlden, U Passant, SH Yen, M DeTure, M Hutton

EXPERIMENTAL NEUROLOGY 184 ( 1 ) 131 - 140 2003.11

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DOI： 10.1016/S0014-4886(03)00393-5

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The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy Reviewed International journal

M Hogg, ZM Grujic, M Baker, S Demirci, AL Guillozet, AP Sweet, LL Herzog, S Weintraub, MM Mesulam, NE LaPointe, TC Gamblin, RW Berry, LI Binder, R de Silva, A Lees, M Espinoza, P Davies, A Grover, N Sahara, T Ishizawa, D Dickson, SH Yen, M Hutton, EH Bigio

ACTA NEUROPATHOLOGICA 106 ( 4 ) 323 - 336 2003.10

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DOI： 10.1007/s00401-003-0734-x

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Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice Reviewed

T Ishizawa, N Sahara, K Ishiguro, J Kersh, E McGowan, J Lewis, M Hutton, DW Dickson, SH Yen

AMERICAN JOURNAL OF PATHOLOGY 163 ( 3 ) 1057 - 1067 2003.9

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DOI： 10.1016/S0002-9440(10)63465-7

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Hippocampal sclerosis dementia with tauopathy Reviewed

TG Beach, L Sue, S Scott, K Layne, A Newell, D Walker, M Baker, N Sahara, SH Yen, MH Hutton, R Caselli, C Adler, D Connor, M Sabbagh

BRAIN PATHOLOGY 13 ( 3 ) 263 - 278 2003.7

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Assembly of tau in transgenic animals expressing P301L tau: alteration of phosphorylation and solubility Reviewed International journal

N Sahara, J Lewis, M DeTure, E McGowan, DW Dickson, M Hutton, SH Yen

JOURNAL OF NEUROCHEMISTRY 83 ( 6 ) 1498 - 1508 2002.12

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DOI： 10.1046/j.1471-4159.2002.01241.x

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Cellular models for tau filament assembly Reviewed International journal

LW Ko, M DeTure, N Sahara, R Chihab, SH Yen

JOURNAL OF MOLECULAR NEUROSCIENCE 19 ( 3 ) 311 - 316 2002.12

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Impaired cell cycle control of neuronal precursor cells in the neocortical primordium of presenilin-1-deficient mice Reviewed International journal

S Yuasa, M Nakajima, H Aizawa, N Sahara, KI Koizumi, T Sakai, M Usami, SI Kobayashi, H Kuroyanagi, H Mori, H Koseki, T Shirasawa

JOURNAL OF NEUROSCIENCE RESEARCH 70 ( 3 ) 501 - 513 2002.11

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DOI： 10.1002/jnr.10430

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Chrysamine G and its derivative reduce amyloid beta-induced neurotoxicity in mice Reviewed International journal

K Ishii, WE Klunk, S Arawaka, ML Debnath, Y Furiya, N Sahara, S Shoji, A Tamaoka, JW Pettegrew, H Mori

NEUROSCIENCE LETTERS 333 ( 1 ) 5 - 8 2002.11

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DOI： 10.1016/S0304-3940(02)00915-1

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Argyrophilic grain disease is a sporadic 4-repeat tauopathy Reviewed International journal

T Togo, N Sahara, SH Yen, N Cookson, T Ishizawa, M Hutton, R de Silva, A Lees, DW Dickson

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 61 ( 6 ) 547 - 556 2002.6

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Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP Reviewed

J Lewis, DW Dickson, WL Lin, L Chisholm, A Corral, G Jones, SH Yen, N Sahara, L Skipper, D Yager, C Eckman, J Hardy, M Hutton, E McGowan

SCIENCE 293 ( 5534 ) 1487 - 1491 2001.8

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DOI： 10.1126/science.1058189

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Rearrangement of microtubule networks by tan bearing missense mutations Reviewed

N Sahara, T Tomiyama, H Mori

NEUROSCIENTIFIC BASIS OF DEMENTIA 113 - 120 2001

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Apolipoprotein E allele-dependent antioxidant activity in brains with Alzheimer's disease Reviewed

A Tamaoka, F Miyatake, S Matsuno, K Ishii, S Nagase, N Sahara, S Ono, H Mori, K Wakabayashi, S Tsuji, H Takahashi, S Shoji

NEUROLOGY 54 ( 12 ) 2319 - 2321 2000.6

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Missense point mutations of tau to segregate with FTDP-17 exhibit site-specific effects on microtubule structure in COS cells: A novel action of R406W mutation Reviewed

N Sahara, T Tomiyama, H Mori

JOURNAL OF NEUROSCIENCE RESEARCH 60 ( 3 ) 380 - 387 2000.5

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DOI： 10.1002/(SICI)1097-4547(20000501)60:3<380::AID-JNR13>3.0.CO;2-5

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The tau mutation (val337met) disrupts cytoskeletal networks of microtubules Reviewed

S Arawaka, M Usami, N Sahara, GD Schellenberg, G Lee, H Mori

NEUROREPORT 10 ( 5 ) 993 - 997 1999.4

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A high incidence of apolipoprotein E epsilon 4 allele in middle-aged non-demented subjects with cerebral amyloid beta protein deposits Reviewed

T Arai, K Ikeda, H Akiyama, C Haga, M Usami, N Sahara, S Iritani, H Mori

ACTA NEUROPATHOLOGICA 97 ( 1 ) 82 - 84 1999.1

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DOI： 10.1007/s004010050958

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Molecular anatomy of tau inclusions with antibodies to specifically recognize tau isoforms Reviewed

S Arawaka, N Sahara, G Lee, H Mori

ALZHEIMER'S DISEASE AND RELATED DISORDERS 259 - 265 1999

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Amyloid-beta-protein isoforms in brain of subjects with PS1-linked, beta APP-linked and sporadic Alzheimer disease Reviewed

A Tamaoka, PE Fraser, K Ishii, N Sahara, K Ozawa, M Ikeda, AM Saunders, Y Komatsuzaki, R Sherrington, G Levesque, G Yu, E Rogaeva, S Shoji, LE Nee, DA Pollen, L Hendriks, JJ Martin, C Van Broeckhoven, AD Roses, LA Farrer, PH St George-Hyslop, H Mori

MOLECULAR BRAIN RESEARCH 56 ( 1-2 ) 178 - 185 1998.5

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DOI： 10.1016/S0169-328X(98)00044-8

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Presenilin 1 cleavage is a universal event in human organs Reviewed

M Okochi, N Sahara, F Kametani, M Usami, T Arai, K Tanaka, K Ishii, A Yamamoto, H Mori

NEUROBIOLOGY OF AGING 19 ( 1 ) S3 - S10 1998.1

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DOI： 10.1016/S0197-4580(98)00045-1

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Variable deposition of amyloid beta-protein (A beta) with the carboxy-terminus that ends at residue valine(40) (A beta 40) in the cerebral cortex of patients with Alzheimer's disease: A double-labeling immunohistochemical study with antibodies specific for A beta 40 and the A beta that ends at residues alanine(42)/threonine(43) (A beta 42) Reviewed

H Akiyama, H Mori, N Sahara, H Kondo, K Ikeda, T Nishimura, T Oda, PL McGeer

NEUROCHEMICAL RESEARCH 22 ( 12 ) 1499 - 1506 1997.12

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DOI： 10.1023/A:1021910729963

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Proteolytic processing of presenilin-1 (PS-1) is not associated with Alzheimer's disease with or without PS-1 mutations Reviewed

M Okochi, K Ishii, M Usami, N Sahara, F Kametani, K Tanaka, PE Fraser, M Ikeda, AM Saunders, L Hendriks, SI Shoji, LE Nee, JJ Martin, C Van Broeckhoven, PH StGeorgeHyslop, AD Roses, H Mori

FEBS LETTERS 418 ( 1-2 ) 162 - 166 1997.11

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DOI： 10.1016/S0014-5793(97)01378-1

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Subset of senile dementia with high incidence of the apolipoprotein E epsilon 2 allele Reviewed

K Ikeda, H Akiyama, T Arai, N Sahara, H Mori, M Usami, M Sakata, T Mizutani, K Wakabayashi, H Takahashi

ANNALS OF NEUROLOGY 41 ( 5 ) 693 - 695 1997.5

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DOI： 10.1002/ana.410410522

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Assignment of Alzheimer's presenilin-2 (PS-2) gene to 1q42.1 by fluorescence in situ hybridization Reviewed

T Takano, N Sahara, Y Yamanouchi, H Mori

NEUROSCIENCE LETTERS 221 ( 2-3 ) 205 - 207 1997.1

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DOI： 10.1016/S0304-3940(96)13290-0

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Chromosomal mapping of presenilin 1 and presenilin 2 gene by fluorescence in situ hybridization (fish)

Yasuko Yamanouchi, Takako Takano, Takuji Shirasawa, Naruhiko Sahara, Hiroshi Mori

Japanese Journal of Human Genetics 42 ( 1 ) 143 1997

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Senile dementia with abundant neurofibrillary tangles without accompanying senile plaques: A subset of senile dementia with high incidence of the APOE epsilon 2 allele Reviewed

K Ikeda, H Akiyama, N Sahara, H Mori, M Usami, M Sakata, T Mizutani, K Wakabayashi, H Takahasi

ALZHEIMER'S DISEASE: BIOLOGY, DIAGNOSIS AND THERAPEUTICS 257 - 265 1997

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Abnormal gel-electrophoretic behavior of presenilin I and its fragment Reviewed

A Yamamoto, N Sahara, M Usami, M Okochi, T Kondo, F Kametani, K Tanaka, Y Yahagi, T Shirasawa, Y Itoyama, H Mori

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 226 ( 2 ) 536 - 541 1996.9

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DOI： 10.1006/bbrc.1996.1390

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Assignment of Alzheimer's presenilin-1 (PS-1) gene to 14q24.3 by fluorescence in situ hybridization Reviewed

T Takano, Y Yamanouchi, N Sahara, T Shirasawa, H Mori

NEUROSCIENCE LETTERS 214 ( 1 ) 69 - 71 1996.8

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DOI： 10.1016/S0304-3940(96)12865-2

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Amyloid beta protein and its 3-kDa fragment are present in the axoplasm fraction of the white matter in human brain Reviewed

T Tokuda, F Kametani, K Tanaka, N Sahara, S Ikeda, N Yanagisawa

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 223 ( 1 ) 165 - 169 1996.6

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DOI： 10.1006/bbrc.1996.0863

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Identification and characterization of presenilin I-467, I-463 and I-374 Reviewed

N Sahara, Y Yahagi, H Takagi, T Kondo, M Okochi, M Usami, T Shirasawa, H Mori

FEBS LETTERS 381 ( 1-2 ) 7 - 11 1996.2

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DOI： 10.1016/0014-5793(96)00054-3

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MODIFIED AMYLOID-BETA PROTEIN ENDING AT 42 OR 40 WITH DIFFERENT SOLUBILITY ACCUMULATES IN THE BRAIN OF ALZHEIMERS-DISEASE Reviewed

Y HARIGAYA, M SHOJI, T KAWARABAYASHI, M KANAI, T NAKAMURA, T IIZUKA, Y IGETA, TC SAIDO, N SAHARA, H MORI, S HIRAI

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 211 ( 3 ) 1015 - 1022 1995.6

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DOI： 10.1006/bbrc.1995.1912

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APP717 MISSENSE MUTATION AFFECTS THE RATIO OF AMYLOID-BETA PROTEIN SPECIES (A-BETA-1-42/43 AND A-BETA-1-40) IN FAMILIAL ALZHEIMERS-DISEASE BRAIN Reviewed

A TAMAOKA, A ODAKA, Y ISHIBASHI, M USAMI, N SAHARA, N SUZUKI, N NUKINA, H MIZUSAWA, S SHOJI, KANAZAWA, I, H MORI

JOURNAL OF BIOLOGICAL CHEMISTRY 269 ( 52 ) 32721 - 32724 1994.12

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BIOCHEMICAL-EVIDENCE FOR THE LONG-TAIL FORM (A-BETA-1-42-43) OF AMYLOID-BETA PROTEIN AS A SEED MOLECULE IN CEREBRAL DEPOSITS OF ALZHEIMERS-DISEASE Reviewed

A TAMAOKA, T KONDO, A ODAKA, N SAHARA, N SAWAMURA, K OZAWA, N SUZUKI, S SHOJI, H MORI

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 205 ( 1 ) 834 - 842 1994.11

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DOI： 10.1006/bbrc.1994.2740

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RACEMIZATION - ITS BIOLOGICAL SIGNIFICANCE ON NEUROPATHOGENESIS OF ALZHEIMERS-DISEASE Reviewed

H MORI, K ISHII, T TOMIYAMA, Y FURIYA, N SAHARA, S ASANO, N ENDO, T SHIRASAWA, K TAKIO

TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 174 ( 3 ) 251 - 262 1994.11

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DOI： 10.1620/tjem.174.251

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OKADAIC ACID ENHANCES ABNORMAL PHOSPHORYLATION ON TAU PROTEINS Reviewed

Y FURIYA, N SAHARA, H MORI

NEUROSCIENCE LETTERS 156 ( 1-2 ) 67 - 69 1993.6

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透明化とPETを用いた新規タウオパチーモデルマウスの全脳3Dイメージング

矢内凛, 南久松丈晴, 下條雅文, 洲崎悦生, 三谷智樹, 上田泰己, 張明栄, 佐原成彦, 樋口真人

Dementia Japan 37 ( 4 ) 2023

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【クライオ電顕が解き明かす神経変性疾患のメカニズム】構造をもとにしたタウPETプローブ開発

佐原成彦, 山口芳樹, 樋口真人

医学のあゆみ 283 ( 13 ) 1144 - 1149 2022.12

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ADモデルマウスを用いたタウのO型糖鎖修飾の解析

飯島順子, 芳賀淑美, 千葉靖典, 植田幸嗣, 西道隆臣, 佐原成彦, 北爪しのぶ

老年精神医学雑誌 33 ( 増刊II ) 240 - 240 2022.11

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新規Rosa26-Knockinタウオパチーマウスを用いたミクログリア動態の探索

矢内凜, 南久松丈晴, 下條雅文, 樋口真人, 佐原成彦

老年精神医学雑誌 33 ( 増刊II ) 255 - 255 2022.11

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認知症制圧のための核酸医薬,mRNA医薬の最前線タウオパチーに対する核酸医薬・mRNA医薬開発に向けてタウ病態の標的分子

佐原成彦

老年精神医学雑誌 33 ( 増刊II ) 167 - 168 2022.11

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認知症制圧のための核酸医薬,mRNA医薬の最前線タウオパチーに対する核酸医薬・mRNA医薬開発に向けてタウ病態の標的分子

佐原成彦

Dementia Japan 36 ( 4 ) 702 - 702 2022.10

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ADモデルマウスを用いたタウのO型糖鎖修飾の解析

飯島順子, 芳賀淑美, 千葉靖典, 植田幸嗣, 西道隆臣, 佐原成彦, 北爪しのぶ

Dementia Japan 36 ( 4 ) 750 - 750 2022.10

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新規Rosa26-Knockinタウオパチーマウスを用いたミクログリア動態の探索

矢内凜, 南久松丈晴, 下條雅文, 樋口真人, 佐原成彦

Dementia Japan 36 ( 4 ) 757 - 757 2022.10

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ダイヤモンド量子計測を用いた生体スピンイメージング応用

石綿整, 佐原成彦

バイオイメージング 31 ( 2 ) 113 - 113 2022.8

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rTg4510認知症モデル動物脳における炎症性アストロサイト病態の画像解析

下條雅文, 南久松丈晴, 高橋真奈美, 田桑弘之, 松下有美, 矢内凛, 湊原圭一郎, 小野麻衣子, 高堂裕平, 張明栄, 佐原成彦, 樋口真人

日本神経化学会大会抄録集(Web) 65th 2022

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Rosa26ノックイン型タウ過剰発現マウスを用いたタウオパチーにおける神経炎症応答解析

矢内凜, 南久松丈晴, 下條雅文, 高堂裕平, 佐原成彦, 樋口真人

日本神経化学会大会抄録集(Web) 65th 2022

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α-synuclein病変の蓄積・伝播を生体脳で可視化する分子プローブの開発

小野麻衣子, 高橋真奈美, 下沢明希, 藤永雅之, 森若菜, 永井裕司, 三村喬生, 熊田勝志, 下條雅文, 高堂裕平, 遠藤浩信, 田桑弘之, 清水宏, 柿田明美, 佐原成彦, 張明栄, 南本敬史, 長谷川成人, 樋口真人

Dementia Japan 35 ( 4 ) 609 - 609 2021.10

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血中のAβおよびその関連分子の由来

北爪しのぶ, 三浦里織, 立田由里子, 武藤優衣, 川口寧, 富本秀和, 佐原成彦, 斉藤貴史, 西道隆臣

Dementia Japan 35 ( 4 ) 649 - 649 2021.10

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アルツハイマー病の病態進行に伴いミクログリアの生理機能が低下する

祖父江顕, 小峯起, 原雄一郎, 遠藤史人, 溝口博之, 渡邊征爾, 村山繁雄, 斉藤貴志, 西道隆臣, 佐原成彦, 樋口真人, 荻朋男, 山中宏二

Dementia Japan 35 ( 4 ) 658 - 658 2021.10

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炎症・ミクログリアと認知症認知症における恒常性ミクログリア動態

佐原成彦

Dementia Japan 35 ( 4 ) 587 - 587 2021.10

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認知症診療の現状と将来展望タウオパチーの多様性を考慮した診断・治療薬開発について現状および今後の展望

佐原成彦

神経治療学 38 ( 3 ) 353 - 353 2021.5

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生体脳イメージングを用いたタウ凝集体を有する神経細胞の脳外排出メカニズムの実証

高橋真奈美, 高橋真奈美, 田桑弘之, 田桑弘之, 漆畑拓弥, 下條雅文, 折原あすみ, 小野麻衣子, 高堂祐平, 冨田裕, 佐原成彦, 須原哲也, 須原哲也, 樋口真人, 樋口真人

脳循環代謝(Web) 33 ( 1 ) 2021

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アルツハイマー病の疾患修飾療法の現状と展望-臨床試験はどこまで進んでいるか抗タウ抗体

佐原成彦

認知症の最新医療 11 ( 1 ) 2021

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Rosa26ノックイン型認知症モデルマウスの作製

南久松丈晴, 下條雅文, 矢内凛, 種村健太郎, 樋口真人, 佐原成彦

日本実験動物技術者協会総会講演要旨集 55th 2021

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認知症診療の現状と将来展望タウオパチーの多様性を考慮した診断・治療薬開発について現状および今後の展望

佐原成彦

神経治療学 37 ( 6 ) S120 - S120 2020.10

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タウオパチーモデルマウスにおけるアミノ酸組成物摂取による神経変性抑止効果

高堂裕平, 佐藤英明, 豊田早紀子, 安居昌子, 湊原圭一郎, 田桑弘之, 漆畑拓弥, 高橋真奈美, 下條雅文, 小野麻衣子, 前田純, 佐原成彦, 青木伊知男, 川崎則子, 神田麻優香, 西村麻依, 長尾健児, 北村明彦, 樋口真人

Dementia Japan 34 ( 4 ) 2020

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急速に運動・認知機能障害が進行し,もの忘れ外来受診後経過3年で死亡した83歳女性剖検例

金田大太, 松原知康, 石井賢二, 徳丸阿耶, 島田斉, 佐原成彦, 須原哲也, 須原哲也, 村山繁雄, 村山繁雄, 齊藤祐子

Dementia Japan 34 ( 4 ) 2020

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Dissecting mechanisms of tauopathy using multimodal imaging techniques

佐原成彦

神経治療学(Web) 37 ( 3 ) 2020

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生体脳イメージングによる病原性蛋白質の脳外排出メカニズムの解明

高橋真奈美, 高橋真奈美, 田桑弘之, 漆畑拓弥, 下條雅文, 冨田裕, 中原仁, 佐原成彦, 樋口真人, 樋口真人

脳循環代謝(Web) 32 ( 1 ) 2020

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認知症のバイオマーカーと早期診断update マルチモーダルイメージングによる認知症発症メカニズムの探索

佐原成彦

神経治療学 36 ( 6 ) S111 - S111 2019.10

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【アルツハイマー型認知症の疾患修飾薬の開発-臨床治験はどの段階を迎えているか】抗タウ抗体

佐原成彦

認知症の最新医療 9 ( 3 ) 144 - 149 2019.7

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アルツハイマー病の進行に関わる新規タンパク質CAPONの機能解析

橋本翔子, 松葉由紀夫, 釜野直子, 三平尚美, 高野二郎, 佐原成彦, 村松慎一, 斉藤貴志, 西道隆臣

Dementia Japan 33 ( 4 ) 2019

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アルツハイマー病を促進させる新規タンパク質CAPONの機能解析

橋本翔子, 松葉由紀夫, 釜野直子, 三平尚美, 高野二郎, 佐原成彦, 村松慎一, 斉藤貴志, 西道隆臣

日本生化学会大会(Web) 92nd 2019

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マーモセット脳で発現するタウのアイソフォームとリン酸化

カク安ニ, SHARMA Govinda, 木村妙子, 木村妙子, 塩澤誠司, 小林玲央奈, 小林玲央奈, 佐原成彦, 石橋みなか, 石垣診祐, 斎藤太郎, 安藤香奈絵, 村山繁雄, 長谷川成人, 祖父江元, 岡野栄之, 岡野栄之, 久永眞市, 久永眞市

日本生化学会大会(Web) 92nd 2019

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【遺伝子改変マウスを用いた新しい創薬・薬理学研究の展開】タウオパチーマウスモデルを用いた脳タンパク質老化モデル評価系の確立

佐原成彦

日本薬理学雑誌 152 ( 1 ) 4 - 9 2018.7

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【脳タンパク質老化と認知症制御】タウオパチーマウスモデルと生体脳イメージング

佐原成彦

細胞 50 ( 6 ) 307 - 310 2018.5

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mGluR5受容体PETを指標としたrTg4510マウスモデル脳における神経機能病態の画像診断

下條雅文, 徳永正希, 田桑弘之, 高堂裕平, 前田純, 漆畑拓也, 南久松丈晴, 張明栄, 青木伊知男, 須原哲也, 佐原成彦, 樋口真人

Dementia Japan 32 ( 3 ) 2018

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Three-dimensional imaging and quantification of neuro-vascular coupling in the mouse cortex

武田寛史, 須貸拓馬, 田桑弘之, 季斌, 佐原成彦, 須原哲也, 樋口真人, 冨田裕, 鈴木則宏, 菅野巖, 正本和人

レーザー学会研究会報告 = Reports the on topical meeting of the Laser Society of Japan 17 ( 25 ) 21 - 25 2017.10

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FTDP-17患者由来iPS細胞を用いたin vitro病態モデルの確立及び表現型解析

中村真理, 渡部博貴, 塩澤誠司, 久永眞市, 佐原成彦, 木村妙子, 宮坂知宏, 高島明彦, 池内健, 岡野栄之

Dementia Japan 31 ( 4 ) 555 - 555 2017.10

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Neuronal activity modulates oligomeric tau-mediated neurodegeneration in FTLD-Tau neurons

Imamura K, Sahara N, Inoue H

58th Annual Meeting of the Japanese Society of Neurology, Kyoto. 2017.9

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【認知症発症前治療のために解明すべき分子病態は何か?】 (第3章)遺伝的視点タウオリゴマーの実態とその遺伝学的因果関係

佐原成彦

実験医学 35 ( 12 ) 2016 - 2022 2017.8

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Oligomeric tau contributes to neurodegeneration in FTLD patient iPHSC-derived neurons

Imamura K, Sahara N, Inoue H

The 40th Annual Meeting of the Japan Neuroscience Society, Chiba. 2017.7

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In vivo brain imaging for studying possible linkage between pathological hallmark of tauopathy and neuronal loss

H. Takuwa, A. Ishikawa, T. Urushihata, T. Minamihisamatsu, M. Tokunaga, M. Shimojo, S. Uchida, I. Matsumoto, M. -R. Zhang, T. Suhara, M. Higuchi, N. Sahara

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 37 193 - 194 2017.4

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【最新遺伝医学研究と遺伝カウンセリングシリーズ2 最新精神・神経遺伝医学研究と遺伝カウンセリング】 (第1章)総論認知症診断ツールとしてのPETイメージング

佐原成彦

遺伝子医学MOOK 別冊 ( 最新精神・神経遺伝医学研究と遺伝カウンセリング ) 80 - 86 2017.4

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Individual neural activity and capillary diameter responses measured in a three-dimensional spatial domain of awake mouse somatosensory cortex

H. Takeda, T. Sugashi, H. Takuwa, B. Ji, N. Sahara, T. Suhara, M. Higuchi, I. Kanno, K. Masamoto

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 37 370 - 371 2017.4

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同一トレーサーでつなぐモデルマウスタウ病態のPET-インビボ蛍光画像解析

田桑弘之, 石川愛, 石川愛, 高堂裕平, 下條雅文, 小野麻衣子, 漆畑拓弥, 漆畑拓弥, 高橋真奈美, 佐原成彦, 須原哲也, 樋口真人

Dementia Japan 31 ( 4 ) 2017

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Tau imaging in patients with ALS/PDC in the Kii Peninsula

Y. Kokubo, H. Shinotoh, H. Shimada, F. Niwa, R. Sasaki, S. Morimoto, H. Endo, S. Kitamura, S. Hirano, I. Aiba, M. Miyamura, N. Sahara, S. Kuzuhara, M. Higuchi, T. Suhara

JOURNAL OF NEUROCHEMISTRY 138 373 - 373 2016.8

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Recent advances in clinical tau PET imaging with [11C]PBB3

島田斉, 北村聡一郎, 丹羽文俊, 木村泰之, 市瀬正則, 山田真希子, 佐原成彦, 樋口真人, 須原哲也, 篠遠仁, 篠遠仁, 遠藤浩信, 遠藤浩信, 石川愛, 石川愛, 平野成樹, 平野成樹, 古賀俊介

千葉医学雑誌 92 ( 3 ) 124 - 124 2016.6

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In vivo evaluation of tau pathologies in patient with progressive supranuclear palsy and healthy subjects with [C-11]PBB3-PET

H. Endo, H. Shimada, Y. Kimura, M. Ichise, M. Ono, H. Shinotoh, F. Niwa, S. Kitamura, K. Takahata, S. Hirano, S. Koga, D. W. Dickson, N. Sahara, M. Yamada, M. Higuchi, T. Toda, T. Suhara

MOVEMENT DISORDERS 31 S383 - S383 2016.6

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In vivo imaging of neuroinflammation in Alzheimer's disease

Makoto Higuchi, Bin Ji, Jun Maeda, Naruhiko Sahara, Tetsuya Suhara

Clinical and Experimental Neuroimmunology 7 ( 2 ) 139 - 144 2016.5

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DOI： 10.1111/cen3.12308

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【脳タンパク質老化と認知症制御】 Alzheimer病マウスモデルを用いた生体脳イメージング研究

佐原成彦

BIO Clinica 31 ( 4 ) 349 - 353 2016.4

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【認知症】診断・バイオマーカータウイメージング PBB3

佐原成彦, 木村泰之

最新医学 71 ( 3月増刊 ) 588 - 594 2016.3

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CONFORMATIONAL HETEROGENEITY OF TAU LESIONS CAPTURED BY PET AND ITS CLINICAL SIGNIFICANCE

Makato Higuchi, Hitoshi Shimada, Naruhiko Sahara, Tetsuya Suhara

NEUROBIOLOGY OF AGING 39 S10 - S11 2016.3

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神経変性疾患領域における基盤的調査研究陽電子放出断層撮影による進行性核上性麻痺の客観的重症度指標の確立

戸田達史, 遠藤浩信, 遠藤浩信, 島田斉, 市瀬正則, 木村泰之, 佐原成彦, 樋口真人, 桑原聡, 須原哲也

神経変性疾患領域における基盤的調査研究平成27年度総括・分担研究報告書 105‐107 2016

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Imaging Multimodalities for Dissecting Alzheimer's Disease: Advanced Technologies of Positron Emission Tomography and Fluorescence Imaging

Masafumi Shimojo, Makoto Higuchi, Tetsuya Suhara, Naruhiko Sahara

FRONTIERS IN NEUROSCIENCE 9 2015.12

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DOI： 10.3389/fnins.2015.00482

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神経放射線診断―最新情報と読影のピットフォール PET Tau PET

ENDO HIRONOBU, ENDO HIRONOBU, SAHARA NARUHIKO, SHIMADA HITOSHI

Clin Neurosci 33 ( 10 ) 1156 - 1158 2015.10

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FTDP‐17 MAPT遺伝子変異症例のタウイメージング―[11C]PBB3 PET‐による検討―

SHINOTOO HITOSHI, SAHARA NARUHIKO, SHIMADA HITOSHI, ZOREKKU TSUBIGUNYU, IKEUCHI KEN, HANYU HARUO, ISHII KENJI, NISHIOKA KEN'YA, KOGA SHUNSUKE, HIGUCHI MAKOTO, SUHARA TETSUYA

核医学 52 ( 3 ) 294 - 294 2015.9

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11C‐PBB3を用いたタウイメージングの当院への導入

山口博司, 山城敬一, 渡辺宏久, 原一洋, 横井孝政, 加藤克彦, 長縄慎二, 須原哲也, 樋口真人, 佐原成彦, 祖父江元

神経治療学 32 ( 5 ) 799 2015.9

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[11C]PBB3 PETによるMAPT遺伝子変異症例のタウイメージング

SHINOTOO HITOSHI, SAHARA NARUHIKO, SHIMADA HITOSHI, ZOREKKU TSUBIGUNYU, IKEUCHI KEN, HANYU HARUO, ISHII KENJI, KOGA SHUNSUKE, HIGUCHI MAKOTO, SUHARA TETSUYA

Dement Jpn 29 ( 3 ) 387 - 387 2015.9

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マウスモデルを用いた,神経障害に関与するタウ病変の生体内評価系の確立

ISHIKAWA AI, ISHIKAWA AI, SAHARA NARUHIKO, TOKUNAGA MASAKI, TAGUWA HIROYUKI, SHIMADA HITOSHI, HIRANO SHIGEKI, HIRANO SHIGEKI, SHINOTOO HITOSHI, KUWABARA SATOSHI, SUHARA TETSUYA, HIGUCHI MAKOTO

Dement Jpn 29 ( 3 ) 418 2015.9

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タウオリゴマー研究の総括と今後の展望

SAHARA NARUHIKO

Dement Jpn 29 ( 3 ) 328 - 328 2015.9

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タウイメージング用PET製剤[11C]PBB3を用いた臨床研究の現状と汎用化体開発の展望

ISHIKAWA AI, FURUKAWA SHOGO, HIRANO SHIGEKI, SHIMADA HITOSHI, SHINOTOO HITOSHI, SAWARA SHIGEHIKO, HIGUCHI MAKOTO, SUHARA TETSUYA

千葉医学雑誌 91 ( 3 ) 149 - 150 2015.6

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タウタンパク質にとって正常と異常の違いは何か?

SAHARA NARUHIKO

日本蛋白質科学会年会プログラム・要旨集 15th 52 2015.5

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脳とこころの分子イメージング分子神経イメージング研究プログラム脳分子動態チーム

HIGUCHI MAKOTO, SAHARA NARUHIKO, MAEDA JUN, KI TAKESHI, MARUYAMA MASAHIRO, TOKUNAGA MASAKI, ONO MAIKO, BARRON ANNA, SHIMOJO MASAFUMI

放射線科学 58 ( 1 ) 18 - 25 2015.2

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認知症のタウPET:一個の細胞の病態が全脳へ波及する過程を追う

HIGUCHI MAKOTO, MARUYAMA MASAHIRO, SHIMADA HITOSHI, SHINOTOO HITOSHI, RI HIN, ONO MAIKO, SAWARA SHIGEHIKO, TAKUWA HIROYUKI, CHO MEIEI, SUHARA TETSUYA

NIRS-R (Natl Inst Radiol Sci) ( 68 ) 13 - 14 2015.1

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The analyze of four pedigrees with MAPT N279K mutation accompanying DAT scan and Tau imaging

IKEDA AYA, NISHIOKA KEN'YA, RI GENTETSU, TAKANASHI MASASHI, YOSHINO HIROYO, FUNAYAMA MANABU, MATSUSHIMA TAKASHI, UENO SHIN'ICHI, KURITA SHOEI, UENO YUJI, SHIMADA HITOSHI, SAHARA NARUHIKO, HIGUCHI MAKOTO, SUHARA TETSUYA, MOTOI YUMIKO, HATTORI NOBUTAKA

パーキンソン病・運動障害疾患コングレスプログラム・抄録集 9th 75 - 75 2015

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[11C]PBB3 PETで推定したタウ蓄積量はアルツハイマー病の認知症重症度を反映する

SHIMADA HITOSHI, SHINOTOO HITOSHI, HIRANO SHIGEKI, FURUKAWA SHOGO, EGUCHI YOKO, TAKAHATA KEISUKE, KIMURA YASUYUKI, KODAKA FUMITOSHI, MARUYAMA MASAHIRO, TAKANO HARUMASA, SAHARA NARUHIKO, YAMADA MAKIKO, IKOMA YOKO, CHO MEIEI, ITO HIROSHI, HIGUCHI MAKOTO, KUWABARA SATOSHI, SUHARA TETSUYA

日本神経学会学術大会プログラム・抄録集 54 ( Suppl. ) S1 - S1 2014.12

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認知症タウ病変のイメージング

HIGUCHI MAKOTO, SHIMADA HITOSHI, MARUYAMA MASAHIRO, SAHARA SHIGEHIKO, SHINOTOO HITOSHI, HIRANO SHIGEKI, ONO MAIKO, CHO MEIEI, SUHARA TETSUYA

Dement Jpn 28 ( 4 ) 446 2014.10

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rTg4510タウオパチーマウスによるタウリガンドPBB3フッ素誘導体の特性評価

ISHIKAWA AI, SAHARA NARUHIKO, TOKUNAGA MASAKI, MINAMIHISAMATSU TAKEHARU, UCHIDA SHOKO, MATSUMOTO IZUMI, HIRANO SHIGEKI, KUWABARA SATOSHI, SUHARA TETSUYA, HIGUCHI MAKOTO

Dement Jpn 28 ( 4 ) 495 2014.10

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生体脳タウイメージング

SAHARA NARUHIKO

Isot News ( 720 ) 7 - 13 2014.4

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TDP‐17の原因遺伝子MAPTの新規挿入変異の同定と生化学解析

KAWAKAMI HIDESHI, MORINO TOYOYUKI, MATSUDA YUKIKO, OSAWA RYOSUKE, HIRAKI KEIKO, KURASHIGE TSUYOSHI, IZUMI YUISHIN, YAMASAKI YU, TAKAHASHI TETSUYA, TAKASHIMA AKIHIKO, SOEDA YOSHIYUKI, MIYASAKA TOMOHIRO, HIGUCHI MAKOTO, SAWARA SHIGEHIKO, SUHARA TETSUYA, SHIMADA HITOSHI, ITO HIDEFUMI, MARUYAMA HIROFUMI

日本生物学的精神医学会誌 266 2014

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Brain Diffusion Tensor Imaging and 31P Spectroscopy of In Vivo Tau P301L Toxicity Mechanisms

Naruhiko Sahara, Pablo Perez, Yan Ren, Huadong Zeng, Jada Lewis, Marcelo Febo

NEUROPSYCHOPHARMACOLOGY 38 S223 - S224 2013.12

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「認知症研究のためのリソース」タウオパチーマウスモデル:創薬研究リソースとしての有効性

SAHARA NARUHIKO

Dement Jpn 27 ( 4 ) 448 2013.10

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基礎認知症研究のためのリソースタウオパチーマウスモデル創薬研究リソースとしての有効性

佐原成彦

Dementia Japan 27 ( 4 ) 448 - 448 2013.10

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Propagation of Tau Pathology in a Model of Early Alzheimer's Disease (vol 73, pg 685, 2012)

Alix de Calignon, Manuela Polydoro, Marc Suarez-Calvet, Christopher William, David H. Adamowicz, Kathy J. Kopeikina, Rose Pitstick, Naruhiko Sahara, Karen H. Ashe, George A. Carlson, Tara L. Spires-Jones, Bradley T. Hyman

NEURON 76 ( 2 ) 461 - 461 2012.10

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前頭側頭型認知症類似の新規タウトランスジェニックマウス作成

KOBE YASUNORI, SHIMADA KOHEI, ISHIGURO KOICHI, MOTOI YUMIKO, HATTORI NOBUTAKA, INOUE RAN, KOJIMA NOBUHIKO, TADA NORIHIRO, KIMURA TETSUYA, MIZOROKI TATSUYA, YAMASHITA TOSHIHARU, TAKASHIMA AKIHIKO, SAWARA SHIGEHIKO, MIZUMA HIROSHI, ONOE HIROTAKA, MIZUNO YOSHIKUNI

順天堂医学 58 ( 1 ) 94 - 95 2012.2

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認知症研究に用いられる動物・細胞実験モデル各論遺伝子改変モデル rTg4510マウス

SAHARA NARUHIKO

日本臨床 69 276 - 281 2011.10

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【認知症学(上)-その解明と治療の最新知見-】基礎編認知症研究に用いられる動物・細胞実験モデル各論遺伝子改変モデル rTg4510マウス

佐原成彦

日本臨床 69 ( 増刊8 認知症学(上) ) 276 - 281 2011.10

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rTg4510 mice

佐原成彦

Japanese journal of clinical medicine 69 ( 0 ) 276 - 281 2011.10

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タウオパチーモデルマウスにおけるリン酸化タウの分布領域の相違と側座核におけるシナプス消失

KOBE YASUNORI, SHIMADA KOHEI, ISHIGURO KOICHI, MOTOI YUMIKO, HATTORI NOBUTAKA, INOUE RAN, KOJIMA NOBUHIKO, TADA NORIHIRO, KIMURA TETSUYA, MIZOROKI TATSUYA, YAMASHITA SHUNJI, TAKASHIMA AKIHIKO, SAHARA NARUHIKO, MIZUMA HIROSHI, ONOE HIROTAKA

順天堂医学 57 ( 3 ) 317 2011.6

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アロキサン投与によるタウTGマウスの不溶性タウおよびHDAC減少を介した微小管安定化と記憶改善

YOSHIIKE YUJI, YAMASHITA SHUNJI, MIZOROGI TATSUYA, MAEDA SUMIHIRO, MURAYAMA MIYUKI, KIMURA TETSUYA, SAHARA NARUHIKO, SOEDA YOSHIYUKI, ROLOVA TAISIA, TAKASHIMA AKIHIKO

Dement Jpn 24 ( 3 ) 181 2010.9

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タウ蛋白を標的とした認知症治療戦略の有効性

SAHARA NARUHIKO

Dement Jpn 24 ( 3 ) 65 2010.9

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タウオパチーモデルマウスでは軸索障害がシナプス障害に先行する

MOTOI YUMIKO, KOBE YASUNORI, SHIMADA KOHEI, ISHIGURO KOICHI, HATTORI NOBUTAKA, KIMURA TETSUYA, TAKASHIMA AKIHIKO, SAHARA NARUHIKO, MIZUMA HIROSHI, ONOE HIROTAKA

Dement Jpn 24 ( 3 ) 183 2010.9

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認知症の阻止を狙った治療薬開発研究タウ蛋白を標的とした認知症治療戦略の有効性

佐原成彦

Dementia Japan 24 ( 3 ) 263 - 263 2010.9

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不安感情障害を示し前頭前野‐側坐核の経路障害を示したタウモデルマウス

KOBE YASUNORI, SHIMADA KOHEI, ISHIGURO KOICHI, MOTOI YUMIKO, HATTORI NOBUTAKA, WADA MAKOTO, TADA NORIHIRO, KOJIMA NOBUHIKO, KIMURA TETSUYA, MIZOROGI TATSUYA, YAMASHITA TOSHIHARU, SAWARA SHIGEHIKO, TAKASHIMA AKIHIKO, INOUE RAN

順天堂医学 55 ( 3 ) 383 2009.9

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アロキサン投与によるタウTGマウスにおける不溶性タウの減少と記憶能力改善

YOSHIIKE YUJI, YAMASHITA SHUNJI, MIZOROGI TATSUYA, MAEDA SUMIHIRO, SAITO AKIKO, OSADA HIROYUKI, MURAYAMA MIYUKI, KIMURA TETSUYA, SAHARA NARUHIKO, SOEDA YOSHIYUKI, ROLOVA TAISIA, TAKASHIMA AKIHIKO

Dement Jpn 23 ( 2 ) 173 2009.8

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不安感と側坐核のシナプス消失を示した野生型タウ過剰発現トランスジェニックマウス

KOBE YASUNORI, SHIMADA KOHEI, ISHIGURO KOICHI, MOTOI YUMIKO, HATTORI NOBUTAKA, WADA MAKOTO, KOJIMA NOBUHIKO, KIMURA TETSUYA, MIZOROGI TATSUYA, YAMASHITA SHUNJI, SAHARA NARUHIKO, TAKASHIMA AKIHIKO, INOUE RAN

順天堂医学 55 ( 2 ) 191 2009.6

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BMP signaling through BMPIRA regulate gliosis in the sub-acute phase

Yamada Masahisa, Naohito Kitamura, Naruhiko Sahara, Akihiko Takashima, Haruhisa Inoue, Ryosuke Takahashi, Yuji Mishina

NEUROSCIENCE RESEARCH 65 S101 - S101 2009

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DOI： 10.1016/j.neures.2009.09.439

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不安感と側坐核のシナプス消失を示した野生型タウ過剰発現トランスジェニックマウス

KOBE YASUNORI, SHIMADA KOHEI, ISHIGURO KOICHI, MOTOI YUMIKO, HATTORI NOBUTAKA, WADA MAKOTO, KOJIMA NOBUHIKO, KIMURA TETSUYA, MIZOROGI TATSUYA, YAMASHITA SHUNJI, SAHARA NARUHIKO, TAKASHIMA AKIHIKO, INOUE RAN

日本神経学会総会プログラム・抄録集 50th 169 2009

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恐怖感消失を示した野生型タウ過剰発現トランスジェニックマウス

KOBE YASUNORI, SHIMADA KOHEI, ISHIGURO KOICHI, MOTOI YUMIKO, HATTORI NOBUTAKA, WADA MAKOTO, KIMURA TETSUYA, YAMASHITA SHUNJI, SAHARA NARUHIKO, TAKASHIMA AKIHIKO

Dement Jpn 22 ( 2 ) 173 2008.8

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タウを介したシナプス消失と神経脱落

KIMURA TETSUYA, FUKUDA TETSUYA, SAHARA NARUHIKO, YAMASHITA SHUNJI, MIZOROGI TATSUYA, MURAYAMA MIYUKI, YOSHIIKE YUJI, ARAI TETSUAKI, AKIYAMA HARUHIKO, TAKASHIMA AKIHIKO

Dement Jpn 22 ( 2 ) 169 2008.8

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Parallel induction of synapse loss and neuronal loss in tau transgenic mice

Tetsuya Kimura, Tetsuya Fukuda, Naruhiko Sahara, Shunnji Yamashita, Tatsuya Mizoroki, Miyuki Murayama, Yuji Yoshiike, Akihiko Takashima

NEUROSCIENCE RESEARCH 61 S122 - S122 2008

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Morphological analysis of human tau transgenic mice showing age-dependent learning disorders

Tetsuya Fukuda, Tetsuya Kimura, Tetsuaki Arai, Shunji Yamashita, Tatsuya Mizoroki, Yung-Mi Park, Miyuki Murayama, Naruhiko Sahara, Haruhiko Akiyama, Akihiko Takashima

NEUROSCIENCE RESEARCH 58 S175 - S175 2007

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タウ線維中間体

MAEDA SUMIHIRO, SAHARA NARUHIKO, TAKASHIMA AKIHIKO

Dement Jpn 20 ( 3 ) 262 - 270 2006.12

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野生型ヒトタウタンパク過剰発現マウスにおける加齢依存性学習障害を引き起こすリン酸化タウの分布と脳活動の解析

FUKUDA TETSUYA, KIMURA TETSUYA, YAMASHITA TOSHIHARU, MIZOROGI TATSUYA, BOKU SEIBI, MURAYAMA MIYUKI, SAWARA SHIGEHIKO, TAKASHIMA AKIHIKO

Dement Jpn 20 ( 2 ) 170 2006.8

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マウス脳における新規タウーアンチセンス遺伝子の定量的解析

UENO HITOMI, SAWARA SHIGEHIKO, MURAYAMA MIYUKI, MIZOROGI TATSUYA, BOKU SEIBI, YAMASHITA TOSHIHARU, KAWAI JUN, HAYASHIZAKI YOSHIHIDE, TAKASHIMA AKIHIKO

Dement Jpn 20 ( 2 ) 170 2006.8

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生体脳におけるCHIP/Hsp90/Hsp40とタウ蛋白代謝との関連性について

SAHARA SHIGEHIKO, MURAYAMA MIYUKI, MIZOROGI TATSUYA, FUKUDA TETSUYA, KIMURA TETSUYA, SAITO YOKO, MURAYAMA SHIGEO, TAKASHIMA AKIHIKO

日本痴呆学会誌 19 ( 2 ) 138 2005.8

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タウタンパク質か粒状凝集体の構造解析とヒト脳における統計学的解析

MAEDA SUMIHIRO, SAHARA SHIGEHIKO, SAITO YUKO, MURAYAMA SHIGEO, IKAI ATSUSHI, TAKASHIMA AKIHIKO

日本痴呆学会誌 19 ( 2 ) 136 2005.8

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プレセニリン1家族性変異による断片化及びγセクレターゼ活性への作用

SHIMOJO MASAFUMI, SHIMOJO MASAFUMI, YOSHIIKE YUJI, SAHARA SHIGEHIKO, MURAYAMA MIYUKI, ICHINOSE HIROSHI, TAKAHASHI AKIHIKO

日本痴呆学会誌 19 ( 2 ) 132 2005.8

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痴呆症の最新情報―治せる痴呆を見逃さないために≪変性疾患の治療に向けて≫アルツハイマー型痴呆の研究最前線―その発症機序はどこまでわかったか

SAHARA NARUHIKO, TAKASHIMA AKIHIKO

内科 95 ( 5 ) 873 - 878 2005.5

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Recent advances in experimental modeling of the assembly of tau filaments

LW Ko, M DeTure, N Sahara, R Chihab, IE Vega, SH Yen

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 1739 ( 2-3 ) 125 - 139 2005.1

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DOI： 10.1016/j.bbadis.2004.09.004

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Mechanism of AB induced cytotoxicity: Toxic AB aggregate associates with cell membrane via positive charge clusters

K Ishizuka, N Sahara, DT Chui, M Murayama, Y Yoshiike, A Takashima

NEUROBIOLOGY OF AGING 25 S149 - S150 2004.7

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Cellular models for tauopathies

SH Yen, M DeTure, N Sahara, LW Ko

NEUROBIOLOGY OF AGING 25 S7 - S7 2004.7

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Insulin dysfunction induces abnormal tau hyperphosphorylation through two distinct mechanisms: Implications for diabetes and Alzheimer's disease

E Planel, N Sahara, Y Tatebayashi, T Launey, K Ishiguro, K Duff, A Takashima

NEUROBIOLOGY OF AGING 25 S42 - S43 2004.7

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Assembly of filamentous tau aggregates in conditional transfectants of human neuronal lineage that overproduce wild-type human brain tau in triple isoforms

LW Ko, T Rush, N Sahara, JS Kersh, M DeTure, WL Lin, C Easson, YD Connor, SHC Yen

NEUROBIOLOGY OF AGING 25 S262 - S263 2004.7

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Mechanism of neurofibrillary tangle formation: Tau accumulation and fibril formation

A Takashima, S Maeda, M Murayama, N Sahara, DH Chui, E Planel, Y Tatebayashi

NEUROBIOLOGY OF AGING 25 S66 - S67 2004.7

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Early behavioral abnormalities in a mouse model of FTDP-17

YA Tatebayashi, T Tominaga, T Mizoroki, E Planel, N Sahara, DH Chui, A Takashima

NEUROBIOLOGY OF AGING 25 S249 - S249 2004.7

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Possible functions of human 3 repeat tau isoform in transgenic mice with regionally specific expression

N Sahara, T Mizoroki, Y Tatebayashi

NEUROBIOLOGY OF AGING 25 S425 - S425 2004.7

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The analysis of tauopathy mice model.

SAHARA NARUHIKO, LIN W-L, DICKSON D W, YEN S-H

遺伝子医学 7 ( 1 ) 17 - 22 2003.3

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【ここまで解った神経変性疾患の最先端研究-アルツハイマー,パーキンソン病を中心に】アルツハイマー病タウオパチーマウスモデルの解析

佐原成彦, Lin Wen-Lang, Dickson Dennis W, Yen Shu-Hui

遺伝子医学 7 ( 1 ) 17 - 22 2003.3

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タウオパチーマウスモデルの解析 (特集ここまで解った神経変性疾患の最先端研究アルツハイマー,パーキンソン病を中心に) -- (アルツハイマー病)

佐原成彦, Lin Wen-Lang, Dickson Dennis W

遺伝子医学 7 ( 1 ) 17 - 22 2003.3

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hSOD1遺伝子導入マウスにおけるAβ神経細胞毒性の減弱効果

ISHII KAZUHIRO, SAHARA SHIGEHIKO, KATO ICHIRO, TAMAOKA AKIRA, ARAWAKA SHIGEKI, FURIYA YOSHIKO, SHOJI SHIN'ICHI, YOSHIMOTO TAKASHI, MORI HIROSHI

臨床神経学 42 ( 12 ) 1333 - 1333 2002.12

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Relationship of motor deficits, neurofibrillary tangles, neurodegeneration, and tau biochemistry in the P301L tau transgenic mice

J Lewis, E McGowan, N Sahara, H Melrose, J Knight, C Zehr, SH Yen, DW Dickson, M Hutton, PN Tariot, R Loy

NEUROBIOLOGY OF AGING 23 ( 1 ) S238 - S238 2002.7

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Temporal expression and phosphorylation of tau in P301L mutant tau transgenic mice

N Sahara, J Lewis, E McGowan, DW Dickson, M Hutton, SHC Yen, G Lee

NEUROBIOLOGY OF AGING 23 ( 1 ) S552 - S553 2002.7

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A cell model for neurofibrillary degeneration in Alzheimer's disease

LW Ko, T Rush, N Sahara, C Easson, M DeTure, SHC Yen

NEUROBIOLOGY OF AGING 23 ( 1 ) S507 - S507 2002.7

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Cross-talk between APP and tau in transgenic mice

M Hutton, J Lewis, D Dickson, WL Lin, L Chisholm, A Corral, G Jones, SH Yen, N Sahara, K Goodwin, L Skipper, D Yager, C Eckman, J Hardy, E McGowan

NEUROBIOLOGY OF AGING 23 ( 1 ) S567 - S567 2002.7

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嗜銀性顆粒痴呆は孤発性4リピートタウオパチーである

都甲崇, 佐原成彦, YEN Shu-Hui, COOKSON Natalie, HUTTON Mike, DE SILVA Rohan, ANDREW Lees, DICKSON DENNIS W

Neuropathology : official journal the Japanese Society of Neuropathology 22 109 - 109 2002.5

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A human neuronal cell culture model for tauopathy using conditional transgene expression of multiple tau isoforms

LW Ko, T Rush, N Sahara, C Easson, SHC Yen

MOLECULAR BIOLOGY OF THE CELL 12 514A - 514A 2001.11

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Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.

DW Dickson, J Lewis, WL Lin, L Chisholm, A Corral, AG Jones, SH Yen, N Sahara, L Skipper, D Yager, C Eckman, J Hardy, M Hutton, E McGowan

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 60 ( 5 ) 503 - 503 2001.5

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老年痴呆関連蛋白に関する基礎医学的調査

MORI HIROSHI, TOYAMA TAKAMI, SAHARA NARIHIKO, FURUYA YOSHIKO

大和証券ヘルス財団研究業績集 24 112 - 116 2001.3

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The effect of tau mutation on cytoskeletal networks of microtubules and cell organelles

H Mori, N Sahara, T Tomiyama, S Arawaka, T Yamashita, S Kosaka, H Takama, G Lee

MOLECULAR BIOLOGY OF THE CELL 10 266A - 266A 1999.11

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Molecular cloning of bovine pressenilin cDNA and phylogenetic analysis of presenilin genes.

SAHARA NARUHIKO, MORI HIROSHI

医学のあゆみ 189 ( 1 ) 37 - 42 1999.4

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系統学的見地からみたプレセニリンの蛋白構造に関する生物学的意義 (4月第1土曜特集 Alzheimer病研究の動向)

佐原成彦, 森啓

医学のあゆみ 189 ( 1 ) 37 - 42 1999.4

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【Alzheimer病研究の動向】系統学的見地からみたプレセニリンの蛋白構造に関する生物学的意義

佐原成彦, 森啓

医学のあゆみ 189 ( 1 ) 37 - 42 1999.4

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Presenilin 1 affects the metabolism of C-terminal fragment derived from Alzheimer's amyloid precursor protein(APP) in PC12 cells.

MORI HIROSHI, KAMETANI FUYUKI, TANAKA KIKUKO, OKOUCHI MASAYASU, SAHARA NARUHIKO

代謝系疾患調査研究班アミロイドーシス分科会 1998年度研究報告書 148 - 151 1999

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プレセニリン蛋白質の系統発生学的解析

佐原成彦, 荒若繁樹, 森啓

神経化学 37 ( 3 ) 571 - 571 1998.9

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Effects of presenilin-1 on the metabolism of Alzheimer amyloid precursor protein.

MORI HIROSHI, KAMETANI FUYUKI, TANAKA KIKUKO, USAMI MIHOKO, SAHARA NARUHIKO, OKOUCHI MASAYASU

代謝系疾患調査研究班アミロイドーシス分科会 1997年度研究報告書 104 - 107 1998.3

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Effects of presenilin-1 on the metabolism of Alzheimer amyloid precursor protein.

MORI HIROSHI, KAMETANI FUYUKI, TANAKA KIKUKO, USAMI MIHOKO, SAHARA NARUHIKO, OKOUCHI MASAYASU

代謝系疾患調査研究班平成9年度研究報告書 183 - 186 1998

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Alzheimer's presenilin 1 is a fetal protein that serves a neuroprotective function

M Okochi, M Usami, N Sahara, F Kametani, K Tanaka, S Takashima, KS Kosik, H Mori

JOURNAL OF NEUROCHEMISTRY 69 S4 - S4 1997

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アルツハイマー病原因遺伝子プレセニリン1蛋白(PS-1)の同定

宇佐美美穂子, 佐原成彦, 亀谷富由樹, 大河内正康, 山本明広, 田中喜久子, 森啓

神経化学 35 ( 3 ) 350 - 351 1996.9

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Identification of Alzheimer disease etiologic gene presenilin1 protein (PS-1).

USAMI MIHOKO, SAHARA SHIGEHIKO, KAMETANI FUYUKI, OKOUCHI MASAYASU, YAMAMOTO AKIHIRO, TANAKA KIKUKO, MORI HIROSHI

神経化学 35 ( 3 ) 350 - 351 1996.9

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脳プレセニリン蛋白の構造と機能

森啓, 佐原成彦, 大河内正康, 亀谷富由樹, 宇佐美美穂, 田中喜久子, 山本明広, 白沢卓二

日本分子生物学会年会プログラム・講演要旨集 19 48 - 48 1996.8

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Function and structure of the brain presenilin protein.

MORI KEI, SAHARA SHIGEHIKO, OKOUCHI MASAYASU, KAMETANI FUYUKI, USAMI MIHOKO, TANAKA KIKUKO, YAMAMOTO AKIHIRO, SHIROSAWA TAKUJI

日本分子生物学会年会プログラム・講演要旨集 19th 48 1996.7

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細胞内に出現するAβについて

宇佐美美穂子, 佐原成彦, 森啓

神経化学 34 ( 2 ) 44 - 45 1995.6

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On the A.BETA. expressed in the cells.

USAMI MIHOKO, SAHARA SHIGEHIKO, MORI TAKASHI

神経化学 34 ( 2 ) 44 - 45 1995.6

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TAU AGGREGATION BY METAL-CATALYZED OXIDATION

N SAHARA, Y FURIYA, K OZAWA, H MORI

JOURNAL OF NEUROCHEMISTRY 65 S41 - S41 1995

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ANALYSES OF AMYLOID BETA-PROTEIN IN-VIVO AND IN-VITRO BY ENZYME-LINKED-IMMUNOSORBENT-ASSAY AND MASS-SPECTROMETRY

A TAMAOKA, A ODAKA, Y ISHIBASHI, M USAMI, N SUZUKI, N SAHARA, N SAWAMURA, S SHOJI, H MORI

JOURNAL OF NEUROCHEMISTRY 65 S75 - S75 1995

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Synthesis of tau proteins using the baculovirus expression system.

USAMI MIHOKO, FURUYA YOSHIKO, SAHARA SHIGEHIKO, MORI HIROSHI

神経化学 33 ( 1 ) 638 - 639 1994.9

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The trial of Alzheimer disease diagnosis by tau measurement of the cerebrospinal fluid.

FURIYA YOSHIKO, HIRAI SHUNSAKU, HOSODA KENJI, SAHARA SHIGEHIKO, USAMI MIHOKO, MORI HIROSHI

神経化学 33 ( 1 ) 320 - 321 1994.9

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アルツハイマー病原因遺伝子の解明にむけて

佐原成彦, 森啓

Mol Med 31 ( 2 ) 229 - 230 1994

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On role of signal sequence in secretion of beta A 4 proteins to extacellular.

USAMI MIHOKO, SAHARA SHIGEHIKO, MARUYAMA TAKASHI, YOSHIKAWA KAZUAKI, YOSHIOKA NOBORU, MORI HIROSHI

神経化学 32 ( 1 ) 490 - 491 1993.10

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Research Projects

Elucidation of the mechanisms of age-related changes in the brain environment

Grant number：23H02825

2023.4 - 2027.3

System name：Grants-in-Aid for Scientific Research

Research category：Grant-in-Aid for Scientific Research (B)

Awarding organization：Japan Society for the Promotion of Science

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Grant amount：\18460000 （ Direct Cost: \14200000 、 Indirect Cost：\4260000 ）

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Elucidation of the mechanisms of age-related alternations in the brain environment

Grant number：23K27516

2023.4 - 2027.3

System name：Grants-in-Aid for Scientific Research

Research category：Grant-in-Aid for Scientific Research (B)

Awarding organization：Japan Society for the Promotion of Science

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Grant amount：\18460000 （ Direct Cost: \14200000 、 Indirect Cost：\4260000 ）

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点鼻タウワクチンによる脳内免疫応答の解明とナノ粒子のベクター利用

Grant number：21H02807

2021.4 - 2024.3

System name：科学研究費助成事業基盤研究(B)

Research category：基盤研究(B)

Awarding organization：日本学術振興会

井上治久, 佐原成彦, 渡辺亮

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Grant amount：\17420000 （ Direct Cost: \13400000 、 Indirect Cost：\4020000 ）

アルツハイマー病や前頭側頭型認知症をはじめとする高齢者の認知症は、今後、人口の超高齢化とともに増加の一途を辿ることが想定され、その対策は重要な課題となっている。その認知症の大多数において、タウ蛋白凝集体の蓄積が特徴的な病変として認められることから、タウ蛋白が蓄積する疾患は、タウオパチーと総称される。多くの研究から、認知症は、発症する前に予防することが重要であることがわかっており、これまで、我々は、タウオパチーモデルマウスにおいて、点鼻ワクチン投与によって脳内の抗タウ抗体価の上昇、タウ蛋白蓄積の減少、グリア炎症の改善、脳萎縮の改善、認知機能の改善が見られることを報告した(Takeuchi, et al.,npj Vaccines 5, 28, 2020)。
本年度は、タウマウスモデルの人工授精によるコロニーの整備、ウイルスワクチンベクターの作製、マウス脳シングルセル解析基盤の整備を実施した。

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ニューロン－ミクログリア連関の破綻を起因としたタウ蛋白質相転移メカニズムの解明

Grant number：21H00446

2021.4 - 2023.3

System name：科学研究費助成事業新学術領域研究(研究領域提案型)

Research category：新学術領域研究(研究領域提案型)

Awarding organization：日本学術振興会

佐原成彦

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Grant amount：\9360000 （ Direct Cost: \7200000 、 Indirect Cost：\2160000 ）

老年性認知症病態の大半を占める凝集性タウタンパク質の脳内蓄積は神経機能障害や細胞脱落と密接に関連していることが知られているが、どのように生理的に微小管結合能を有するタウが自己凝集能を獲得し、病的なタウが特定脳領域より拡散・伝播するのか、その技術的特異点は明らかになっていない。本研究では、タウ蛋白質相転移（正常から異常への変換点）がタウ毒性の本体であると仮定し、昨年から継続して、生体イメージング技術を用いてrTg4510マウスにおけるタウ病変発症の技術的特異点を同定することを目的としている。
昨年度は、タウPET imagingによるrTg4510マウスにおけるタウ病変伝播の規則性を探索することで一定の成果を挙げた。また、タウ沈着形成前の早期病態変化として神経細胞のミクログリアによる貪食作用の検出を目指し、複数のミクログリアマーカータンパク質の病理学的検討を行い、タウ病態とミクログリア活性化の関連性を明らかとした。

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Investigating mechanisms of tau-induced neurotxicity

Grant number：19K06896

2019.4 - 2022.3

System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

Research category：Grant-in-Aid for Scientific Research (C)

Awarding organization：Japan Society for the Promotion of Science

Sahara Naruhiko

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Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

Neuropathological observations revealed the existence of abundant inclusions with the properties of amyloid fibrils. Most neurodegenerative diseases are defined by multiple types of inclusion consisting of aggregated forms of protein or peptide called proteinopathy. The microtubule-associated protein tau abnormally aggregates into intracellular, filamentous inclusions (NFTs) in brains of individuals with neurodegenerative diseases including Alzheimer’s disease (AD). NFTs are closely associated with the severity of brain function loss in AD. Thus, making tau protein a target in the treatment of AD has become a major therapeutic strategy. Here, we established cellular and mouse models of tauopathy showing cell-cell propagation and pathological tau accumulation. In addition, tauopathy-linked microglial phenotypic change distinct was observed in the mouse model of tauopathy. These models will be essential tools for investigating mechanisms of tau-induced neurotoxicity.

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マルチモーダル生体イメージングシステムを活用したタウ蛋白質相転移メカニズムの解明

Grant number：19H05437

2019.4 - 2021.3

System name：科学研究費助成事業新学術領域研究(研究領域提案型)

Research category：新学術領域研究(研究領域提案型)

Awarding organization：日本学術振興会

佐原成彦

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Grant amount：\8580000 （ Direct Cost: \6600000 、 Indirect Cost：\1980000 ）

老年性認知症病態の大半を占める凝集性タウタンパク質の脳内蓄積は神経機能障害や細胞脱落と密接に関連していることが知られているが、どのように生理的に微小管結合能を有するタウが自己凝集能を獲得し、病的なタウが特定脳領域より拡散・伝播するのか、その技術的特異点は明らかになっていない。我々は、ヒト家族性認知症で発見された変異型タウ蛋白質を過剰発現し、生後６ヶ月でタウ蛋白質病変に伴う脳萎縮、神経炎症を呈するタウオパチーマウスを用いて、生体イメージングによる病態発症メカニズムの解析を行ってきた。本研究では、タウ蛋白質相転移（正常から異常への変換点）が神経機能障害を引き起こす毒性の本体であると仮定し、神経細胞内で起こるタウ蛋白質相転移点をタウオパチーマウスの生体イメージング実験系を用いて明らかにすることを目的とした。これまでにタウ標識化合物[18F]PM-PBB3がアルツハイマー病、進行性核上性麻痺、皮質基底核変性症、ピック病並びにrTg4510マウスのタウ蛋白質病変を陽電子放出断層撮像(PET)にて可視化できることを報告した(Tagai et al. 2021)。PM-PBB3はアルツハイマー病以外のタウオパチーにおいて高い検出感度で病態を可視化できることが特徴であり、凝集性タウ蛋白質線維に選択性の高い蛍光リガンドとしても活用できる。PM-PBB3の凝集性タウ蛋白質線維に対する結合特性を調べるため、クライオ電顕で得られた立体構造情報をもとにDocking simulationを行なったところ、特定のクロスβ構造に選択的に結合することが明らかとなった(Mishra et al. 2020)。これらの研究成果をもとに、初期のタウ蛋白質相転移を検出する上で特定の蛋白質立体構造が同定された場合、Docking simulationなどの計算技術が活用されることが期待される。

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Brain Protein Aging and Dementia Control(International Research Activities Supporting Program)

Grant number：15K21714

2015.11 - 2019.3

System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Research category：Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Awarding organization：Japan Society for the Promotion of Science

Sobue Gen, YANAI kazuhiko, TAKASHIMA akihiko, HASEGAWA masato, ONODERA osamu, OKANO hideyuki, SAHARA naruhiko, ADACHI hiroaki, ANDO kanae, AKAMATSU wado, UCHIYAMA keiji, OHTA etsuro, OKADA yohei, ONO masahiro, KAIBUCHI kozo, KATO koichi, SAKAGUCHI suehiro, TAINAKA kazuki, TAKAHASHI ryosuke, TANAKA hiromitsu, NAGAI yoshitaka, HASHIMOTO tadafumi, HASEGAWA takafumi, HAMADA kozo, FUKADA masaki, FUKUDA mitsunori, FURUKAWA yoshiaki, MATSUI hideaki, MIZUTA kotaro, MOCHIZUKI hideki, YAMADA kaoru, MORISHITA hideaki, HISANAGA shinichi

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Grant amount：\58760000 （ Direct Cost: \45200000 、 Indirect Cost：\13560000 ）

Firstly, we established the secretariat and relating committees in order to promote the international joint research and global communications.During the past four years, 43 researchers presented their research achievements abroad, and 24 distinguished foreign researchers were invited to Japan by our programs. With more than 500 participants in total, we held two international symposiums, the international workshop, the international tau symposium as well as the joint meeting with PACTALS to promote the joint research and the establishment of research networks on a global basis.
Notably, we succeeded to publish eBook composed by 22 papers in “Frontiers in Neuroscience.” This was highly effective to appeal our research achievements to the world. Through our original website, annual reports of research activities and annual newsletters, our research achievements were also effectively and successfully notified to researchers, especially those of relating to our research fields.

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Investigation for understanding the mechanisms of tau-induced neurotoxicity by using multimodal in vivo imaging techniques

Grant number：15K06793

2015 - 2017

System name：Grants-in-Aid for Scientific Research

Research category：Grant-in-Aid for Scientific Research (C)

Awarding organization：Japan Society for the Promotion of Science

Sahara Naruhiko, Ishikawa Ai

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Authorship：Principal investigator Grant type：Competitive

Grant amount：\5200000 （ Direct Cost: \4000000 、 Indirect Cost：\1200000 ）

Association of tau deposition with neurodegeneration in Alzheimer’s disease and related tau-positive neurological disorders indicates contribution of tau aggregates to neurotoxicity. In vivo visualization of tau accumulation would offer a reliable, objective index to aid in the diagnosis of tauopathy and to assess the disease progression. Positron emission tomography (PET) imaging of tau lesions is currently available using several tau PET ligands. Because most tau PET ligands have the property of an extrinsic fluorescent dye, these ligands are considered to be useful for both PET and fluorescence imaging. Using these advanced imaging techniques, we developed a unique diagnostic platform of in vivo imaging of tau-, neuroinflammation-PET, and volumetric MRI. Brains of living mice can be used to monitor their volume, pathological tau accumulation and neuroinflammation. Moreover, live cell imaging with two-photon microscopy allows us to capture NFT formation and neuronal death in mice.

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Development of imaging-based diagnostic procedures for brain protein aging

Grant number：26117008

2014 - 2018

System name：Grants-in-Aid for Scientific Research

Research category：Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Awarding organization：Japan Society for the Promotion of Science

Sahara Naruhiko, Higuchi Makoto, Matsumoto Gen, Minamimoto Takafumi, Aoki Ichio

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Authorship：Principal investigator Grant type：Competitive

Grant amount：\50830000 （ Direct Cost: \39100000 、 Indirect Cost：\11730000 ）

Aims of this project are to develop biomarkers and to establish diagnostic procedures for brain protein aging. During past 5 years, rTg4510 transgenic (tg) mice expressing P301L mutated tau and non-tg mice were examined with brain MRI and PET imaging. PET studies with [11C]PBB3 and [11C]AC-5216 tracers, which labeled tau pathology and TSPO, revealed age-dependent increases, and correlated with age-dependent volume reduction in the forebrain on MRI. Histochemical analyses confirmed the relevance of pathological tau accumulation and elevated TSPO immunoreactivity in putative microglia. Our results indicate that in vivo imaging of animal models is able to explore the temporospatial relationship among tau deposition, neuroinflammation and neuronal loss. Non-invasive PET imaging combined with transgenic mouse models can be a powerful experimental tool to investigate mechanisms of neurodegenerative diseases and evaluate therapeutic interventions.

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タウオパチーの病態解明とタウ凝集中間体を標的とした治療戦略

Grant number：20500328

2008 - 2010

System name：科学研究費補助金(基盤研究(C))

Research category：基盤研究(C)

Awarding organization：文部科学省

佐原成彦

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Authorship：Principal investigator Grant type：Competitive

Grant amount：\3640000 （ Direct Cost: \2800000 、 Indirect Cost：\840000 ）

近年のアルツハイマー病を含めた神経変性疾患の病態解明と治療法確立を目指した研究の進捗状況には目覚しいものがある。一方で、本年2008年7月にシカゴにて開催された国際アルツハイマー学会では、「アミロイド仮説」を基盤としたアルツハイマー病の治療戦略がことごとく失敗に終わり、新たな標的を求めて戦略を練りなおす必要性に迫られているという現実に直面していることに多くの研究者たちが衝撃を受けていた。このような世界的な研究の流れの中で、老人斑の主要構成成分であるベーダアミロイドではなく、神経原線維変化の主要構成成分であるタウ蛋白の凝集中間体を標的とした治療法の開発は、多くの研究者たちにとって、魅力的な戦略のひとつとなってきた。本年度は、上述した学会において治療効果を評価するのに必須である実験マウスモデルについて、その認知機能の程度とタウ蛋白の生体内における生化学的な挙動変化との間の相関性について報告した。また、タウ蛋白の凝集中間体の物性解析についての総論を論文発表した。さらに、タウ蛋白の細胞毒性という観点から細胞モデルにおけるタウ蛋白凝集中間体の挙動を解析し、その成果報告の準備を進めている。本研究代表者は海外赴任に伴い残念ながら日本国内での科学技術研究費の交付資格を喪失してしまうが、今後もアルツハイマー病を含めた神経変性疾患の病態解明を目的として、とくにタウ蛋白依存性の神経変性疾患発症過程を同定し、治療法の確立に貢献したいと考えている。

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神経原線維変化形成機構

Grant number：18023038

2006 - 2007

System name：科学研究費助成事業特定領域研究

Research category：特定領域研究

Awarding organization：日本学術振興会

高島明彦, 佐原成彦, 木村哲也, 福田哲也, 吉池裕二, 前田純宏

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Grant amount：\8600000 （ Direct Cost: \8600000 ）

本年度は、加齢に伴うタウの蓄積と脳機能障害との関係を調べることを目的とした。
前脳領域特異的なCaMKIIプロモーター下で野生型ヒトタウ蛋白を過剰発現するTgマウスを作製し、行動実験・MRI・免疫組織化学の手法によりTgマウスの加齢に伴う脳機能の変化を解析した。Tgマウスは内在性タウの2-3倍の発現を示したが、組織学的な検討から、高齢になっても神経脱落と神経原線維変化は検出されなかった。このTgマウスは12ヶ月令では学習障害を示さなかったが老齢期(25ヶ月令)において運動機能非依存的なMorris water mazeによる場所(空間)学習課題における有意な障害が観察された。生存中に脳のどの部位に障害が起きているかを調べるため、機能的マンガン増強MRI法(神経活動に伴ったマンガンイオンの蓄積を利用した機能的MRI法)を用いてマウス脳活動の可視化を試みた。その結果Tgマウスにおいて嗅内野の神経活動と加齢による学習能力の低下が有意に相関することが示された。さらにこの嗅内野では可溶性の過剰リン酸化タウ蛋白が神経細胞内に蓄積し、シナプス数の減少を起こしていることがわかった。従って、神経原線維変化形成や神経脱落ではなくリン酸化タウ蛋白の蓄積が脳機能障害に関与する可能性が示唆された。これまでの、試験管内タウ凝集研究とあわせて考えると、微小管に結合しているタウは過剰リン酸化によって微小管からはずれ過剰リン酸かタウが細胞質で凝集体形成を始める。過剰リン酸化タウは線維状構造物を形成する前に多量体、顆粒状凝集隊を形成する。これら、2つの凝集体がシナプス減少に寄与している可能性が示唆された。

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神経原線維変化形成機構

Grant number：17025045

2005

System name：科学研究費助成事業特定領域研究

Research category：特定領域研究

Awarding organization：日本学術振興会

高島明彦, 佐原成彦, 木村哲也, 福田哲也, 吉池裕二

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Grant amount：\4600000 （ Direct Cost: \4600000 ）

神経原線維変化形成機序を明らかにすることにより老人性認知症の治療法および診断法を確立することをこの研究課題では目指している。今年度はリコンビナントヒト4リピートタウをヘパリンと共にインキュベーションしたタウ凝集をチオフラビン蛍光およびAFMを用いて観察し、顆粒状タウ構造物がタウ線維形成の中間体として存在することを見いだした。
チオフラビン蛍光測定からタウ凝集には3つのフェーズが存在することが示された。最初期はチオフラビン蛍光が増大しない、すなわちβシート構造をまだとらない時期、それに引き続きチオフラビン蛍光の増大さらに定常状態への移行が観察された。最初のフェーズではタウはジスルフィド結合を介したオリゴマーを形成する、その後そのオリゴマーがβシート構造を持つ結合により顆粒状構造物となることがAFM下で観察された。この顆粒状構造物の濃度が増大するとタウの線維形成が起こることがIn vitroで見いだされた。このことから、顆粒状構造物がタウ線維の中間体構造物であることが示された。次に、異なるBraakステージの前頭葉標本から顆粒状構造物を精製しその量的変化を検討した。ヒト脳ホモジェネートを抗タウ抗体を用いたアフィニティーカラムを用いて顆粒状タウ構造物を含むタウ蛋白を粗精製した後、ショ糖濃度勾配法によって分離精製された。驚くべきことに顆粒状タウ構造物はBraakステージ1の段階で既に前頭葉で増大を示しており、このことは神経原線維変化形成のかなり前に顆粒状構造物の形成増大が起きていることを示している。すなわち、この顆粒状構造物の形成はアルツハイマー病になる以前に起きており、この構造体を指標にアルツハイマー病発症の早期診断が可能となるかもしれない。

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Mechanism of NFT formation

Grant number：13210147

2001 - 2004

System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Priority Areas

Research category：Grant-in-Aid for Scientific Research on Priority Areas

Awarding organization：Japan Society for the Promotion of Science

TAKASHIMA Akihiko, SAHARA Naruhiko, ISHIZUKA Koko, CHUI De-Hua, PLANEL Emmanuel

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Grant amount：\60000000 （ Direct Cost: \60000000 ）

We generated the mouse overexpressing human 4 repeat tau driven by PDGF-β promoter, which contains V337M frontotemporal dementia-17(FTDP-17) mutation. The amount of expression was about 5-10% of endogenous mouse tau, and the accumulation of hyper-phosphorylated tau was seen in the hippocampus CA2 and 3 region and the cerebral cortex at 11 month old. At this age tau in Tg mouse became insoluble for SDS and form filamentous structure, and Tg mouse could form NFT with aging. The decrease in the neuronal activity in the hippocampus was observed in the electrophysiological experiments. In addition, Tg mice didn't show habituation, and significantly stay longer in open arm in elevated plus maze test. Thus, it was clarified that NFT formation reduced neural activity in hippocampus and caused behavioral disorder.
In case of the other tau Tg mouse overexpressed human 4 repeat tau with the R406W mutation under control of CAMK II promoter, the mouse model also showed NFT like pathology accompanying with memory deficit, which pathophysiological features are very similar to the patient of AD and R406W. In addition, we could find the activation of GSK-3b and JNK in neurons, which accumulate hyperphosphorylated tau, suggesting that GSK-3 and JNK might be involved in NFT formation.
To confirm the involvement of GSK-3 and JNK on NFT formation, we expressed JNK, deltaMEKK, GSK-3b, and human tau in COS7 cells. Tau showed the increased phosphorylation at 12 phosphorylation sites, including AT100 immunoreactive site, which is known as a peculiar antigen of PHF-tau seen in AD. SDS insoluble materials showed anti-phospho-tau immunoreactive aggregates. Thus, an excessive phosphorylation of Tau by GSK-3 β and JNK took part in NFT formation. In addition, when GSK-3 was activated by β amyloid, tau TG mouse resulted in the neurofibrillary tangle formation, the synapse loss, and the neuron death.

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タウを介したプレセニリンの神経変性調節機構の解明

Grant number：12780586

2000

System name：科学研究費補助金(奨励研究(A))

Research category：奨励研究(A)

Awarding organization：文部科学省

佐原成彦

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Authorship：Principal investigator Grant type：Competitive

Grant amount：\1500000 （ Direct Cost: \1500000 ）

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Neuropathological study on Abeta toxicity using transgenic mice with human APP

Grant number：11680742

1999 - 2000

System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

Research category：Grant-in-Aid for Scientific Research (C)

Awarding organization：Japan Society for the Promotion of Science

MORI Hiroshi, SUZUKI Misao, SAHARA Naruhiko, TOMIYAMA Takami

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Grant amount：\3700000 （ Direct Cost: \3700000 ）

Amyloid plaques and neurofibrillary tangles are neuropathological and molecular hallmarks for Alzheimer's disease (AD). Their presence is highly important to understand the etiology of the disease. Making model mice is undoubtedly crucial to examine the molecular mechanism how to develop plaque formation and cell death in cerebral tissues and to study a potent therapeutic drug. We tried to make a mouse that bears cerebral amyloid plaques by cross the mutated APP717 (referred to as London mutation) mouse and the mutated PS1 mouse. Both mutations were generated by PCR with human APP and PS1 cDNA templates. These two DNA constructs for transgenic mice were integrated in prion promoter plasmid vector (from Dr. D.Borchelt, Jonhs Hopkins Univ.). We succeeded in generate three lines of mice with human APP717 and two lines of mice with human mutated PS1. The lines were established to show their genetic and protein expression. Amyloid protein was exmained and established to show neurotoxicity using fetal hippocampal neurons derived from these mice. An antagonic effect was found to be associated with crystamine G that is an analogue of congo red to bind amyloid fibril in AD brain.

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プレセニリン1蛋白質と神経細胞死を結びつける情報伝達経路の同定

Grant number：10780489

1998 - 1999

System name：科学研究費助成事業奨励研究(A)

Research category：奨励研究(A)

Awarding organization：日本学術振興会

佐原成彦

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Authorship：Principal investigator Grant type：Competitive

Grant amount：\2000000 （ Direct Cost: \2000000 ）

本研究では、家族性アルツハイマー病(FAD)の原因遺伝子産物として発見されたプレセニン1(PS1)を研究対象の中心において、ADにおける選択的神経細胞死のメカニズムを解明することを目的とした。さらに最近、第17染色体遺伝子に連鎖したパーキンソニズムを伴う家族性前頭側頭葉型痴呆(FTDP-17)の原因遺伝子としてタウの変異が同定されたことから、この2つの痴呆疾患で共通に起こる神経細胞死の経路を同定しようと試みた。
平成10年度は、生体脳内においてPS1変異とAβ42分子種産生増加との関連性を明らかにした。また、ヒト以外にウシ、マウスのプレセニリン遺伝子をクローニングし、プレセニリンホモログの系統発生学的解析を行いFADにみられるミスセンス変異のアミノ酸部位が保存されていること、生体内で断片化して存在するプレセニリン蛋白質の切断部位近傍のアミノ酸配列は種を越えて保存されていることなどが明らかにされ、プレセニリン研究における発生生物学的研究の重要性があらためて浮き彫りにされた。平成11年度は、FTDP-17において同定されたアミノ酸置換型変異タウを用いて細胞生物学的検討を行った。その結果、2種類の変異型タウ(Val337Met,Arg406Trp)が、微小管ネットワーク構築を阻害すること、その効果は、3つの微小管結合部位をもつ短いタイプのアイソフォームでのみ見られることなどが明らかにされ、タウのアミノ酸置換が直接微小管ネットワーク構築を阻害することによって神経細胞死が起こる可能性を示した。
本研究課題の成果は、変異型プレセニリンと変異型タウのそれぞれの機能の一端を明らかにしたことであり、タウの脳内蓄積という点でFTDP-17と共通項を持つADにおいてもプレセニリンとタウを介した神経細胞死の経路が存在していることが予測される。

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プレセニリン断片の細胞生物学的解析

Grant number：10163246

1998

System name：科学研究費助成事業特定領域研究(A)

Research category：特定領域研究(A)

Awarding organization：日本学術振興会

森啓, 佐原成彦

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Grant amount：\1800000 （ Direct Cost: \1800000 ）

アルツハイマー病の主要原因遺伝子プレセニリン1の機能については神経病変である老人斑分子(Aβ1-42/43)の高進やあるいは細胞死を誘起する可能性が議論されているが、実際にヒト脳組織を用いた検索は少ない。これまで細胞内蛋白分解の視点からアルツハイマー病を検討してきたが、プレセニリン1突然変異によってプレセニリン1自身の蛋白分解が変化するという議論に明瞭な研究成果を得ることができた。プレセニリン1自身はヒト脳組織内では大きく2つの断片の複合体として存在しているが、プレセニリン1異常である早期発症型家族性アルツハイマー病でもその代謝に変化がなかった。すなわちプレセニリン1自身の代謝異常ではなく、その機能変化が痴呆発症を引き起こすことが結論された。また、この家族性をしめす脳組織の初期病理変化がAβ1-42/43であることを確定することができた。最近議論され始めたアポトーシスとの関連が特に重要視され始めているが、この問題について、脳組織内のプレセニリン1のカスパーゼ断片と調べると共に、カスパーゼ-3ノックアウトマウスを用いた研究を進行させてきている。その結果、細胞内プレセニリン蛋白の95%以上は26kの安定な断片として存在していることを見出した。さらに最近、断片化が2種類あることがハーバード大学のグループによって提唱されているが、この新しい断片化はCaspase-3による分解であることから、アポトーシス細胞死に関連することが示唆されてきた。われわれは現在この結論を支持する結果をカスパーゼ-3ノックアウトマウスから得ていないが、さらに検討をすすめることを計画している。

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The effect of presenilin-1 on cerebral amyloid protein

Grant number：09835024

1997 - 1998

System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

Research category：Grant-in-Aid for Scientific Research (C)

Awarding organization：Japan Society for the Promotion of Science

MORI Hiroshi, SAHARA Nobuhiko

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Grant amount：\3500000 （ Direct Cost: \3500000 ）

The effect of presenilin-1 on cerebral amyloid b protein
Amyloid beta protein (Abeta) in senile plaque and amyloid angiopathy is important not only for neuropathological hallmarker but also for the causal gene (APP) product. The possible interaction of APP and presenilin-1, another causal gene localized on chromosome 14, becomes the crutial issue for the etiology of the disease. Here we analyzed the effect of presenilin-1 on cerebral Abeta deposition in patients with Alheimer's disease.
Abeta is composed of Abeta1-4O and Abeta1-42/43. Accumulating evidence shows that the causal mutation of presenilin-1 induces the higher concentration of Abeta1-42/43 than Abeta1-40. However, the present analysis showed also that the mutation causes significantly higher Abeta1-40 in addition to Abeta1-42/43 in AD patients. This may be related with the recent findings on multiple function for presenilm-1 that (1) presenhlin-1 null mice show both defects on Abeta1 production and developmental segmentation, (2) presenilin-1 could bind APP, beta-catenin and GSK3beta molecules. Thus, it is highly likely that presenilin-l affect both Abeta species. This remains to be studied using transgenic mouse model in future.

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プレセニリン断片の細胞生物学的解析

Grant number：09267243

1997

System name：科学研究費助成事業重点領域研究

Research category：重点領域研究

Awarding organization：日本学術振興会

森啓, 佐原成彦, 山本明広, 亀谷富由樹, 宇佐美美穂子

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Grant amount：\2000000 （ Direct Cost: \2000000 ）

早期発症型家族性アルツハイマー病の原因遺伝子プレセニリン1(PS1)は467残基のアミノ酸からなる膜タンパク質であることが知られている。トランスジェニックマウスおよび培養細胞等の解析から、このPS-1の突然変異がアミロイド線維の主成分であるAβ42を増加させることが明らかとなってきた。このことは、PS-1がAβの前駆体タンパク質(APP)の代謝過程に大きく関与していることを示唆している。このPS-1蛋白が家族性アルツハイマー病脳内では正常脳内とは異なった代謝をする結果APP代謝の異常を引き起こすことが示唆する報告もあり、この点について検討した。また、アポトーシスによる細胞死機構がアルツハイマー病の神経変性死についても関与することが議論されており、未決着の状態であったことから調査を進めた。
その結果、ヒト脳内ではPS-1蛋白はPS-1遺伝子の異常(点突然変異)の有無に関係なく、28kDaのNTFと18kDaのCTFの2つのペプチド断片に分解された状態で存在することが確定した。また、アポトーシスに関連したCaspase-3断片は分子量43kDaをしめすププチド断片であることが提唱されているが、この分子量を目安に解析したところ、PS-2断片にはあるが、PS-1断片には見出されなかった。今後はAPPとPS-1あるいはPS-2との直接・間接を含めた結合様式を明らかにすることが重要であり、この点に焦点をあてていきたい。

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脳由来の新神経細胞生存維持因子の単離

Grant number：07264244

1995

System name：科学研究費助成事業重点領域研究

Research category：重点領域研究

Awarding organization：日本学術振興会

森啓, 佐原成彦, 宇佐美美穂子

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Grant amount：\1600000 （ Direct Cost: \1600000 ）

胎生18日齢のラット大脳皮質神経細胞の初代培養を用いた.細胞密度は24-well培養皿に低密度(0.8×105/cm2)で播種した.これに細胞播種と同時にウシ脳ホモジェネート調製液を加え,4日間培養後にMTTキットにて生存細胞を定量し,コントロールと比較した.ウシ脳ホモジェネートの調製はPBSにプロテアーゼ阻害剤を加えたものを用い,ブレンダーで懸濁し,10万g遠心上清を得た.この上清の30-50%硫安画分沈殿を50mMTris-HCl pH7.6に溶解し,脱塩後に50mMTris-HCl pH7.6で平衡化したDEAE sephacel に吸着させ,0-0.12M NaClの分画を抽出した.この抽出液を硫安で濃縮した後,ケ-ル濾過 Sephacryl S-100HR(φ2.5×100cm)にて分取したサンプルから分子量別に4つの生物活性ピーク(A,B,C,D)を得た.40K付近の peak A を集め,脱塩後に10mMリン酸バッファーにて平衡化したResouce Q に吸着させ,0-0.3M NaClの linea gradient にて抽出した.Resouce Qの0-0.3M NaCl linea gradient にて活性が3peakに分かれた.各フラクションの抗NSE抗体(Enzo Biochem)と抗CPB-1(=AnnexinV)抗体(Kowa)によるWestern blottingの結果,NSE(neuron specific enorase)やCPB-1による活性peak以外に 0.08-0.1M NaCl付近に新しい活性中心を発見した.硫安を加え1.2M硫安サンプルとし,疎水性カラムphenyl superoseに吸着させ,1.2-OM硫安の linear gradient で抽出し,ゲル濾過 superdex 75(φ10×300mm)を行った.新しい活性は phenyl superose にて0.7-0.5M硫安分画みられ,次の superdex 75 のゲル濾過にて約30K付近に来ることが判った.SDS-PAGEの銀染色にて候補の活性物質は約22Kと約29Kと考えられた.現在,ウシ脳約4KgのLarge scaleで精製し,蛋白の同定中である.

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脳神経細胞死誘因物質の分子生物学的研究

Grant number：06272238

1994

System name：科学研究費助成事業重点領域研究

Research category：重点領域研究

Awarding organization：日本学術振興会

森啓, 瀧尾廣士, 佐原成彦, 山本明広, 宇佐美美穂子

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Grant amount：\2300000 （ Direct Cost: \2300000 ）

脳細胞の死はいわゆるプログラムされたもの(apoptosis)と条件死がある。血管機能の異常にもとずく変化として酸素欠乏や栄養欠損があるが、これ以外にも各種成長因子の低下もしくはそれらのレセプター異常も重要な因子である。われわれは、ラット脳神経の初代培養において神経細胞の密度も1つの因子であることを見いだした。このことは、脳に由来する未来の因子が低密度の神経細胞能勢依存に作用しているとの作業仮説をたてて脳組織に存在する新しい神経細胞維持因子を探索しようとしている。用いて方法としては、ラット胎仔脳(18日齢)の初代培養にラット脳及び牛脳ホモジェネートを加える。4日間の培養後、MTTキット(Dojin)をもちいて細胞生存率を求める。脳ホモジェネートはさらに、遠心操作、硫安分画、ガラムクロマトグラフィーによる分画操作を実施した。いまだ研究は完了していないが、われわれが観察している活性因子はCMセルロースでの溶出条件の違いから既知のBDNFとは異なることが示唆された。この因子は遠心上清に回収され、pH5.5の酸性処理によって遠心上清に残る点ではこれまで知られている成長因子とよく似た性質があると推察される。また、同因子は30-50%の硫安分画にあることから、basic FGFとも異なることがわかる。DEAEセファロースでは0.2MNaClにて溶出されることから酸性タンパクであると結論した。現在、生理的条件下におけるグル濾過をすることによって、おおよその分子量を決定しつつある。

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Study on the mechanism of amyloid betaprotein deposition in Alzheimer's disease brain

Grant number：05680690

1993 - 1994

System name：Grants-in-Aid for Scientific Research Grant-in-Aid for General Scientific Research (C)

Research category：Grant-in-Aid for General Scientific Research (C)

Awarding organization：Japan Society for the Promotion of Science

MORI Hiroshi, TAKIO K, SAHARA N, USAMI M

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Grant amount：\2000000 （ Direct Cost: \2000000 ）

We have biochemically purified Abeta from brains of two unrelated familial Alzheimer's disease (FAD) pedigrees with the APP717 mutation (Val to lle) and from two sporadic AD brains and characterized them by means of mass spectrometry and EIA assay. We observed two types of Abeta, the short-tail form (Abeta1-40) and the long-tail form (Abeta1-42/43) in sporadic AD brains (Mori, H., Takio, K., Ogawara, M.& Selkoe, D.J., Mass spectrometry of purified amyloid beta protein in Alzheimer's disease, J.Biol.Chem., 267 : 17082-17086,1992). We examined Abeta in FAD brains and sporadic AD brains, and found that the ratio of the long-tail form of Abeta (Abeta1-42/43) to total Abeta was increased in FAD brains. These in vivo results were confirmed in vitro using cultured cells transfected with three kinds of APP cDNAs bearing the APP717 mutations (Val to lle, Gly of Phe).Taken together with the hypothesis that Abeta1-42/43 functions as a "seed" that increases the kinetics of amyloid fibril formation (Jarrett, J.T.& Lansbury, P.T.Jr.(1993) Cell 73,1055-1058), we conclude that the APP717 missense mutation promotes the increased accumulation of Abeta1-42/43 in the brain, which results in the enhancement of amyloid fibril formation from soluble Abeta. These findings provide a causal relationship between this FAD genotype and the pathological phenotype of Abeta deposition and senile plaque fromation.

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