公募シンポジウム４：タウ蛋白の病態生理学的機能
Symposium4 : Pathophysiology of tau protein |
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| 2020/9/10 16:12～16:32 Zoom A
SY4-01
正常タウの解析から認知症脳におけるタウの異常性を考える
Considering the abnormality of pathological tau; lessons from physiological tau!
*宮坂 知宏1、萩田 彩香1、御園生 裕明2
1. 同志社大学生命医科学部 神経病理学研究室、2. 同志社大学脳科学研究科 チャネル病態生理部門
*Tomohiro Miyasaka1, Ayaka Hagita1, Hiroaki Misono2
1. Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, 2. Laboratory of Ion Channel Pathophysiology, Graduate School of Brain Science, Doshisha University
Microtubule associated protein tau binds on microtubules to stabilize them in neurons. Tau is also known to form insoluble inclusions in affected neurons in the brains of aging-related dementia, tauopathy. In contrast to stacks of studies for pathological tau abnormalities, including phosphorylation, aggregation, etc., only little knowledge of the behavior of physiological tau in vivo has been provided.
A prime example is the distribution of tau in vivo. It had not been demonstrated for a long time, although it had been believed to localize in axons, due to technical limitations to visualize pre-aggregated tau in brain tissues. This demonstration is important because tau inclusions are in fact mostly formed in somatodendrites of affected neurons. To investigate where tau localizes physiologically in adult brains and how this mis-localization occurs in model mice, we developed antibodies that can label non-pathological tau with high sensitivity. Using these tools, we found that endogenous mouse tau is explicitly expressed during the perinatal period and precisely localized in axons. In contrast, exogenouslly expressed human tau in tau-Tg mouse brains exhibited uncontrolled expression beyond perinatal period, and mis-localized into somatodendrites, thereby forming pathologies. We also replicated the findings in a culture model that tau localizes to the axon only when expressed in immature neurons. Thus, ectopic expression of tau in adult neurons may be critical for its somatodendritic mis-localization, a key step of the tauopathy.
Now we are also trying to demonstrate whether the phosphorylation can affect the functions of tau on microtubules in vivo. Here, we would like to discuss the abnormalities of tau that have been highlighted by the studies of healthy brains.
| | 2020/9/10 16:32～16:52 Zoom A
SY4-02
タウオパチー治療のための点鼻ワクチンの開発
Nasal vaccine for the treatment of tauopathy
*今村 恵子1,2,3、竹内 啓喜1、佐原 成彦4、井上 誠5、田平 武6、樋口 真人3、井上 治久1,2,3,7
1. 京都大学iPS細胞研究所、2. 理化学研究所バイオリソース研究センター、3. 理化学研究所革新知能統合研究センター、4. 量子医学・医療部門 放射線医学総合研究所、5. 大日本住友製薬、6. 順天堂大学、7. 京都大学医学部附属病院先端医療研究開発機構
*Keiko Imamura1,2,3, Hiroki Takeuchi1, Naruhiko Sahara4, Makoto Inoue5, Takeshi Tabira6, Makoto Higuchi3, Haruhisa Inoue1,2,3,7
1. Center for iPS Cell Research and Application (CiRA), Kyoto University, 2. iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC) , 3. Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), 4. Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 5. Sumitomo Dainippon Pharma Co., Ltd., 6. Department of Diagnosis, Prevention and Treatment of Dementia, Faculty of Medicine, Juntendo University, 7. Institute for Advancement of Clinical and Translational Science, Kyoto University
According to an increment of aging populations, the rates of dementia, including Alzheimer's disease and frontotemporal dementia, are continuously increasing, and development of medication for treatment or prevention of dementia are urgent. Among types of dementia, tau proteins accumulate in the brains of neurodegenerative tauopathies including Alzheimer's disease and frontotemporal lobar degeneration (FTLD-tau). Intracellular and extracellular accumulation of tau, especially tau oligomer, is closely related to the pathogenesis of tauopathy. To prevent dementia caused by tauopathy, we generated a nasal vaccine for gene therapy-based immunotherapy against tau, and verified the effectiveness using FTLD-tau model mice.
Tau vaccines given as nasal drops induced tissue tau-immunoreactive antibody production, and ameliorated cognitive impairment in FTLD-tau model mice. In the hippocampus of immunized mice, in vivo imaging demonstrated suppression of brain atrophy and neuronal inflammation, and postmortem neuropathological analysis presented suppression of phosphorylated tau accumulation and neurotoxic gliosis. The nasal vaccine delivery may provide a therapeutic opportunity for tauopathy, and may contribute to the development of vaccines to control tau-related dementia including Alzheimer's disease and other neurodegenerative diseases.
| | 2020/9/10 16:52～17:12 Zoom A
SY4-03
アルツハイマー病におけるタウ病理の伝播機構解明に向けて
Towards elucidation of propagation mechanism of tau pathology in Alzheimer's disease
*笹栗 弘貴1,2
1. 理化学研究所脳神経科学研究センター、2. 東京医科歯科大学大学院 脳神経病態学
*Hiroki Sasaguri1,2
1. RIKEN Center for Brain Science, 2. Department of Neurology and Neurological Science, Tokyo Medical and Dental University
In neurodegenerative diseases such as Alzheimer's disease (AD), it has been shown that disease-related proteins form aggregates mainly in neuronal cells. These protein aggregates spread through the brain as the diseases progress. Recently, it has been hypothesized that these protein aggregates propagate between cells in similar ways to abnormal prion proteins in prion diseases. AD is the leading cause of dementia, and is pathologically characterized by the accumulation of amyloid β (Aβ) as extracellular plaques, hyper-phosphorylated tau as intracellular neurofibrillary tangles (NFTs), and neuroinflammation, followed by the loss of neuronal cells mainly in the cerebral cortex and hippocampus. Cortical NFTs in AD first appear in transentorhinal region, spread to entorhinal cortex and hippocampal formation, and extend to other cortical regions. Tau pathology correlates with cognitive dysfunctions and brain atrophy in AD patients, suggesting that tau plays important roles in neuronal loss in AD. Therefore, it is important to elucidate the mechanism of propagation of tau pathology to establish therapeutic strategy to prevent clinical progression of AD. To demonstrate propagation of tau pathology in vivo, researchers have innoculated recombinant tau protein or brain homogenates derived from AD patients into AD mouse models that overexpress disease-related proteins. We recently generated next generation AD mouse models that harbor familial AD-related mutations in the mouse App gene which encode amyloid precursor protein (APP). These App knock-in (KI) mice recapitulate amyloid pathology and neuroinflammation in the brain without overexpressing disease-related genes. In addition, we replaced the mouse Mapt gene with the human MAPT gene in these mice to reproduce tau pathology. The doble KI mice lacked overt tau pathology such as NFTs. However, humanization of tau significantly accelerated propagation of AD brain-derived pathological tau compared to wild-type or App-KI mice. We propose that the double KI mice are suitable for studying the mechanism of tau propagation in AD.
| | 2020/9/10 17:12～17:32 Zoom A
SY4-04
タウ病態モデルマウス脳における選択的な抑制性シナプス障害と早期検出
Selective disruption of inhibitory synapses leading to neuronal hyperexcitability at an early stage of tau pathogenesis in a mouse model
*下條 雅文1
1. 量子科学技術研究開発機構 放射線医学総合研究所
*Masafumi Shimojo1
1. National Institutes for Quantum and Radiological Science and Technology
Synaptic dysfunction with aberrant hyperexcitability in cortical circuits is currently hypothesized as a critical pathophysiological process underlying clinical manifestations in Alzheimer's disease (AD) and related neurodegenerative tauopathies. Recent evidence has indicated that abnormalities of synaptic structure and function may associate to an early stage of tau pathology, however, in vivo dynamics of excitatory and inhibitory synapses during disease progress remain to be clarified. In this study, we investigated time-course changes of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by positron emission tomography (PET) imaging along with post-mortem assessment. We demonstrate that radiosignals of [11C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in non-transgenic mice at 2-3 months of age. In contrast, retentions of (E)-[11C]ABP688, a tracer for metabotropic glutamate receptor subtype 5 (mGluR5), were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Postmortem assessment of brain tissues revealed that inhibitory but not excitatory synapses selectively disrupted without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was accompanied 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 synapses in an early stage of tau pathology may be a critical trigger of progressive neurodegeneration, and our PET assessments of inhibitory versus excitatory synapses potentially offer in vivo indices for hyperexcitability and excitotoxicity early in the etiological pathway of neurodegenerative tauopathies.
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