公募シンポジウム

公募シンポジウム認知症スペクトラムにおけるタウアイソフォームの偏りの重層的な理解ーそのメカニズム、バイオマーカー開発と治療介入ー

7月8日（土）　16:00-18:00　Room C 3SY⑤-1 AD脳の4Rから3R tauへの遷移とひろがりは伝播仮説で説明できるのか？ 4R to 3R shift of tau isoforms in AD is explained by prion-like propagation? 内原　俊記¹ 1. 新渡戸記念中野総合病院　脳神経内科・脳神経研究室, 2. 順天堂大学　神経学, 3. 東京医科歯科大学　脳神経病態学 Toshiki Uchihara¹ 1. Neurology Clinic with Neuromorphomics Laboratory, Nitobe Memorial Nakano General Hospital, Tokyo, Japan, 2. Department of Neurology, Juntendo University, 3. Neurology and Neurological Science, Tokyo Medical and Dental University The hierarchal spread of neurofibrillary tangles (NFTs) from the hippocampus to the cortex in Alzheimer disease (AD)/aging brains, initially proposed by Braak, revolutionized our understanding by putatively explaining that tau lesions are unidirectionally extended along neural connections. Because pathological misfolding of tau can serve as a seed to induce identical misfolding on normal tau, this prion-like property is considered to represent a molecular mechanism that may explain lesion spread. However, double-labeling for three repeat (3R) and four repeat (4R) tau demonstrated a profile shift: initially positive only for 4R in early pretangles, gradual involvement of 3R in mature NFTs, and replaced by 3R in ghost tangles. Surprisingly, this profile shift from 4R to 3R tau is shared with the regional spread of NFT around the hippocampus, which is hardly explained by propagation. Some molecules other than tau or non-materialist influences such as neuronal activity may be candidate mechanisms to explain this profile shift. Because this profile shift is shared with brainstem NFTs, it may represent a cell autonomous phenomenon, tightly linked with progression of AD but not necessarily linked with prion-like propagation along neural connections. In addition to sophisticated experimental demonstrations, careful reference to the realities of human brain may be necessary.		7月8日（土）　16:00-18:00　Room C 3SY⑤-2 Do tau pathology and TDP-43 pathology have mechanistic links?: a review of humanneuropathology. 陸　雄一¹ 1. 愛知医科大学　加齢医科学研究所, 2. 名古屋大学大学院　脳神経内科 Yuichi Riku¹ 1. Inst. for Medical Sci. of Aging, Aichi Med. Univ., Aichi, Japan, 2. Dept. of Neurology, Nagoya Univ. Aichi, Japan Neuronal and glial accumulation of tau defines tauopathies, including Alzheimer's disease, Pick Disease, progressive supranuclear palsy, and corticobasal degeneration. Human tau undergoes alternative splicing at several exons, generating 3- and 4-repeat isoforms. Selective accumulation of any or both isoforms corresponds to each disease entity: 3-repeat for Pick disease, mixed 3- and 4-repeat for Alzheimer's disease, and 4-repeat for progressive supranuclear palsy and corticobasal degeneration. Conversely, neuronal accumulation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, which can be collectively termed TDP-43 proteinopathies. Interestingly, postmortem observations revealed concomitant tau pathology in TDP-43 proteinopathies or TDP-43 pathology in tauopathies. The fact indicates pathological overlapping between tauopathies and TDP-43 proteinopathies, and mechanistic links between these two disease groups may be hypothesized. Basic models reproduce tau and TDP-43 double proteinopathy partially but not completely. The difficulty in investigation of the mechanistic links may arise from multifactorial and polygenetic natures of neurodegenerative disorders. Further discovery of shared pathomechanism between tauopathies and TDP-43 proteinopathies may be critical to suggest key therapeutic molecules.

7月8日（土）　16:00-18:00　Room C 3SY⑤-3 アクチン結合蛋白Filamin-Aに着目したタウオパチー病態解明と治療介入 Translational research of tauopathy focusing on actin-binding protein Filamin-A 辻河　高陽^1,2, 佐橋　健太郎¹, 勝野　雅央^1,3 1. 名古屋大学大学院医学系研究科神経内科, 2. 名古屋大学高等研究院, 3. 名古屋大学大学院医学系研究科臨床研究教育学 Koyo Tsujikawa^1,2, Kentaro Sahashi¹, Masahisa Katsuno^1,3 1. Dept. of Neurology, Nagoya Univ., Nagoya, Japan, 2. Institute for Advanced Research, Nagoya Univ., Nagoya, Japan, 3. Dept. of Clinical Research Education, Nagoya Univ., Nagoya, Japan Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by tau aggregation in neurons and glial cells. While amyloid-β lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including 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 has remained elusive. Here, we showed that filamin-A is abundant and co-localized with the aggregated tau in the brains with PSP. We also identified gene duplications and rare single nucleotide variants of Filamin-A gene in cases with PSP. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. Also, reduction of filamin-A corrected aberrant tau levels in the culture cells from cases with PSP. The transgenic mice expressing human filamin-A (FLNA-Tg) showed augmented sarkosyl-insoluble tau and co-localization of filamin-A with tau in the neurons and glial cells. Finally, primary cortical neurons from the FLNA-Tg mice showed tau phosphorylation and defective neurite outgrowth, which were rescued by lentiviral short hairpin RNA-mediated knockdown of filamin-A. Our data suggest filamin-A might be a potential therapeutic target for PSP.		7月8日（土）　16:00-18:00　Room C 3SY⑤-4 Tauopathy modeling for the development of next-generation tau PET tracers 矢内　凜, 南久松　丈晴, 下條　雅文, 樋口　真人, 佐原　成彦量子科学技術研究開発機構脳機能イメージング研究部 Rin Yanai, Takeharu Minamihisamatsu, Masafumi Shimojo, Makoto Higuchi, Naruhiko Sahara Department of Functional Brain Imaging National Institutes for Quantum and Radiological Science and Technology Tauopathy is characterized by the fibrillar tau accumulation in the central nervous system. Current advance of tau PET imaging enables to visualize tau fibrils in living brains. Especially, tau tracer PM-PBB3 (APN-1607) can discriminate non-Alzheimer type tauopathies from Alzheimer’s disease. PM-PBB3 can bind diverse tau fibril conformers and capture high-contrast tau pathologies. Additionally, the results Cryo-EM and docking simulation suggested that selectivity and specificity of ligand binding to diverse tau fibrils. In development of next-generation tau PET tracers, there is a possibility that high selectivity ligands can be made for distinguish 3-repeat, 4repeat, and mixed isoform types. For ligand screening, it is desirable to create model animals that stably reproduce each tauopathy characterized by fibril structures. In reality, it is not easy to generate tauopathy models that recapitulate human tau pathologies. In this talk, I will introduce the utility and the pitfalls of current mouse models and will propose future strategies of mouse modeling to replicate human tauopathies.

7月8日（土）　16:00-18:00　Room C 3SY⑤-5 核酸医薬を用いたタウisoform制御によるタウオパチー治療法開発 Development of therapeutics for tauopathies using antisense modulation of tau isoforms 石垣　診祐滋賀医科大学神経難病研究センター Shinsuke Ishigaki Molecular Neuroscience Research Center, Shiga University of Medical Science Tau is a microtubule-binding protein associated with Alzheimer's disease and tauopathies, including frontotemporal lobar degeneration (FTLD). Based on the number of repeat sequences, tau is divided into 3-repeat (3R) and 4-repeat (4R) isoforms. The accumulation of 4R-tau is linked to FTLD, progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Normalization of increased 4R-tau by introducing an adeno-associated virus (AAV) expressing shRNA against 4R-tau resulted in the recovery of FTLD-like phenotypes in mice. We developed 2'-O, 4'-C-ethylene-bridged nucleic acid (ENA)-modified ASOs (ENA-ASOs) capable of skipping MAPT exon to normalize the 4R/3R-tau ratio. We identified an ENA-ASO, NK-18, that efficiently skips MAPT exon 10 both. Intracerebroventricular administration of NK-18 targeting MAPT exon 10 normalized the imbalanced 4R/3R-tau ratio in FUS-silenced humanized tau mice. We found that it also ameliorated the disease phenotypes of FUS-silenced humanized tau mice, including aberrant behaviors and neurodegeneration. NK-18 remained in the brain, retaining its ability for splicing correction for up to 24 months post-injection with minimal inflammatory reactions. These findings suggest that ENA-ASO targeting MAPT exon 10 has therapeutic potential for 4R-tau-associated tauopathies, including FTLD, PSP, and CBD.