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Shen, Lin-Lin; Li, Wei-Wei; Xu, Ya-Li; Gao, Shi-Hao; Xu, Man-Yu; Bu, Xian-Le; Liu, Yu-Hui; Wang, Jun; Zhu, Jie; Zeng, Fan; Yao, Xiu-Qing; Gao, Chang-Yue; Xu, Zhi-Qiang; Zhou, Xin-Fu; Wang, Yan-Jiang
Neurobiology of disease, December 2019, 2019-12-00, 2019-12-01, Volume: 132Journal Article
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. •p75NTR mediates Aβ-induced neuronal tau hyperphosphorylation.•The calpain/CDK5 and AKT/GSK3β pathways are involved in Aβ/p75NTR-induced tau hyperphosphorylation.•Modulation of p75NTR is a potential therapeutic approach to rescue brain tau pathology in AD.
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