Neurotrophin receptor p75 mediates amyloid β-induced tau pathology

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 (p75^NTR) is a receptor for Aβ and mediates Aβ neurotoxicity, implying that p75^NTR 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 p75^NTR 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/p75^NTR-mediated p-tau levels in neurons. Treatment of male P301L mice with soluble p75^NTR extracellular domain (p75ECD-Fc), which antagonizes the binding of Aβ to p75^NTR, suppressed tau hyperphosphorylation. Taken together, our findings suggest that p75^NTR meditates Aβ-induced tau pathology and is a potential druggable target for AD and other tauopathies.