Neurotrophin receptor p75 mediates amyloid β-induced tau pathology

作者：Lin‐Lin Shen, Weiwei Li, Yali Xu, Shi-Hao Gao, Man‐Yu Xu, Xian‐Le Bu, Yu-Hui Liu, Jun Wang, Jie Zhu, Fan Zeng, Xiu‐Qing Yao, Chang‐Yue Gao, Zhiqiang Xu, Xin‐Fu Zhou, Yan‐Jiang Wang · 发表于：Neurobiology of Disease · 年份：2019 · DOI：10.1016/j.nbd.2019.104567 · 被引用次数：60 · 研究领域：Alzheimer's disease research and treatments、Nerve injury and regeneration、Neurogenesis and neuroplasticity mechanisms

Neurofibrillary tangles of hyperphosphorylated tau protein (p-tau) are a key pathological feature of Alzheimer's disease (AD). Tau phosphorylation is suggested to be secondary to amyloid-beta (Aβ) accumulation. However, the mechanism by which Aβ induces tau phosphorylation in neurons remains unclear. Neurotrophin receptor p75 (p75NTR) is a receptor for Aβ and mediates Aβ neurotoxicity, implying that p75NTR may mediate Aβ-induced tau phosphorylation in AD. Here, we showed that Aβ-induced tau hyperphosphorylation and neurodegeneration, including tau phosphorylation, synaptic disorder and neuronal loss, in the brains of both male wild-type (Wt) mice and male P301L transgenic mice (a mouse model of human tauopathy) were alleviated by genetic knockout of p75NTR in the both mouse models. We further confirmed that the activation or inhibition of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3β (GSK3β) significantly changed Aβ/p75NTR-mediated p-tau levels in neurons. Treatment of male P301L mice with soluble p75NTR extracellular domain (p75ECD-Fc), which antagonizes the binding of Aβ to p75NTR, suppressed tau hyperphosphorylation. Taken together, our findings suggest that p75NTR meditates Aβ-induced tau pathology and is a potential druggable target for AD and other tauopathies.