Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
University of the Chinese Academy of Sciences, Beijing 100049, China.
Sci Transl Med. 2023 Sep 13;15(713):eabo6889. doi: 10.1126/scitranslmed.abo6889.
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.
tau 发病机制是许多神经退行性疾病的标志，包括阿尔茨海默病（AD）。虽然导致患者大脑中 tau 错误折叠和随后 tau 扩散的事件在很大程度上尚不清楚，但创伤性脑损伤（TBI）可能是 tau 介导的神经退行性变的一个风险因素。使用重复 TBI（rTBI）范式，我们报告 rTBI 诱导 PS19 tau 转基因小鼠多个脑区出现磷酸化和错误折叠 tau 的体细胞积累以及神经退行性变，但在野生型（WT）小鼠中则没有。rTBI 加速了年轻 PS19 小鼠和 WT 小鼠的体细胞 tau 病理学，只有在分别接种 tau 原纤维和 AD 脑源性病理性 tau（AD-tau）后才会发生，这表明 tau 种子是 rTBI 诱导的体细胞 tau 病理学所必需的。rTBI 进一步破坏了轴突微管，并在 WT 小鼠的视神经束中诱导了点状 tau 和 TAR DNA 结合蛋白 43（TDP-43）病理学。视神经束中的这些变化与视觉功能下降有关。用一种穿透大脑的微管稳定分子治疗可减少 rTBI 诱导的 WT 小鼠视神经束中的 tau、TDP-43 发病机制和神经退行性变以及视觉功能障碍。用微管稳定剂治疗还可以减轻 AD-tau 接种 WT 小鼠大脑中 rTBI 诱导的 tau 病理学。这些结果表明 rTBI 促进了异常微管组织、病理性 tau 形成和神经退行性变，并表明微管稳定作为 TBI 诱导的神经退行性变的潜在治疗途径。
