阿尔茨海默病(AD)是影响我国人口健康的突出问题，尚无有效防治手段。tau在AD致病中起重要作用，病理性tau呈朊样传播。近年研究显示用tau抗体进行免疫治疗可减轻AD动物模型自发性tau病理并改善记忆，但机制不明，文献推测可能是抗体介导外源致病性tau降解而阻断其向正常神经元的朊样传播。我们预实验显示抗体43D能阻断体内tau朊样传播，并且发现tau病理发生有赖于一定tau水平，而直接降低tau表达可抑制tau病理，因此我们提出抗体治疗主要降低细胞内源性tau的假设。本项目拟首先利用tau朊样传播细胞模型，体外筛选对tau传播有明确阻断作用的tau抗体，进行动物体内验证，然后利用体外细胞模型，通过分析细胞tau变化和抑制胞膜Fc受体、敲除胞内Fc受体TRIM21、抑制蛋白酶体及自噬等，验证上述假设，探讨免疫治疗阻断tau朊样传播的分子机制，为tau病理相关神经退行性疾病治疗提供实验基础。

Alzheimer’s disease (AD), a neurodegenerative disorder with no cure so far and the most common cause of dementia, has been emerging as one of the most challenging health problems and a huge socioeconomic burden as the Chinese population ages. As evidence shows the correlation between severity of dementia and extent of tau pathology load in the brain, tau has been selected to target for therapeutic intervention. Recent studies have shown that passive immunization with antibodies targeting tau may reduce tau pathology load and improve cognition in transgenic mouse models of AD. The therapeutic benefits of tau antibodies was thought to attribute to removal of pathological tau and inhibition of the induction of templated misfolding of normal tau by pathogenic tau which has been taken up in healthy neurons, possibly by antibody-mediated degradation of exogenous pathogenic tau within recipient neurons. However, the mechanism proposed above leaves unresolved the question why treatment with tau antibody reduces the levels of not only total tau but soluble tau as well. Given that direct reduction of tau protein expression by antisense oligonucleotides mitigates and even reverses pathological tau in vivo and inhibits tau seeding in vitro, we hypothesize that the major contribution of tau antibodies to block tau pathology propagation is to facilitate the degradation of, instead of exogenous tau aggregates, endogenous tau and thus reduce total tau level. To test this hypothesis, we propose in the present application to first screen panels of antibodies targeting either total or phosphorylated tau for inhibition of tau seeding in HEK293 cells expressing full-length, P301L mutated human 0N4R tau which is C-terminally tagged with venus, and to verify, with 1-3 of the antibodies showing highest efficacy in vitro, the inhibition of tau spread in vivo, and then to study the molecular mechanisms underlying the inhibitory effect of tau antibodies on prion-like spread of tau. The mechanistic study will be carried out by using molecular biology techniques in vitro in cell models, emphasizing on identification of the pathway by which endogenous tau is degraded and reduced. The completion of the proposed study will shed light on novel mechanisms of tau immunization, and help develop therapeutic strategy for the treatment of AD and related neurodegenerative disorders.