神经退行性变
陶氏病
发病机制
神经科学
慢性创伤性脑病
τ蛋白
创伤性脑损伤
微管
生物
转基因小鼠
病理
视束
医学
转基因
阿尔茨海默病
细胞生物学
视神经
疾病
毒物控制
遗传学
精神科
伤害预防
基因
脑震荡
环境卫生
作者
Xinyi Zhao,Wen Zeng,Hong Xu,Zihan Sun,Yingxin Hu,Beibei Peng,Jim McBride,Jiangtao Duan,Juan Deng,Bin Zhang,Soojung Kim,Bryan Zoll,Takashi Saito,Hiroki Sasaguri,Takaomi C. Saido,Carlo Ballatore,Haishan Yao,Zhaoyin Wang,John Q. Trojanowski,Kurt R. Brunden,Virginia M.‐Y. Lee,Zhuohao He
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2023-09-13
卷期号:15 (713)
被引量:6
标识
DOI:10.1126/scitranslmed.abo6889
摘要
Tau pathogenesis is a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD). Although the events leading to initial tau misfolding and subsequent tau spreading in patient brains are largely unknown, traumatic brain injury (TBI) may be a risk factor for tau-mediated neurodegeneration. Using a repetitive TBI (rTBI) paradigm, we report that rTBI induced somatic accumulation of phosphorylated and misfolded tau, as well as neurodegeneration across multiple brain areas in 7-month-old tau transgenic PS19 mice but not wild-type (WT) mice. rTBI accelerated somatic tau pathology in younger PS19 mice and WT mice only after inoculation with tau preformed fibrils and AD brain-derived pathological tau (AD-tau), respectively, suggesting that tau seeds are needed for rTBI-induced somatic tau pathology. rTBI further disrupted axonal microtubules and induced punctate tau and TAR DNA binding protein 43 (TDP-43) pathology in the optic tracts of WT mice. These changes in the optic tract were associated with a decline of visual function. Treatment with a brain-penetrant microtubule-stabilizing molecule reduced rTBI-induced tau, TDP-43 pathogenesis, and neurodegeneration in the optic tract as well as visual dysfunction. Treatment with the microtubule stabilizer also alleviated rTBI-induced tau pathology in the cortices of AD-tau-inoculated WT mice. These results indicate that rTBI facilitates abnormal microtubule organization, pathological tau formation, and neurodegeneration and suggest microtubule stabilization as a potential therapeutic avenue for TBI-induced neurodegeneration.
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