Neurotrophin receptor p75 mediates amyloid β-induced tau pathology.

Neurotrophin receptor p75 mediates amyloid β-induced tau pathology. Neurobiol Dis. 2019 Aug 05;:104567 Authors: Shen LL, Li WW, Xu YL, Gao SH, Xu MY, Bu XL, Liu YH, Wang J, Zhu J, Zeng F, Yao XQ, Gao CY, Xu ZQ, Zhou XF, Wang YJ Abstract 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 med...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research