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 (A beta) accumulation. However, the mechanism by which A beta induces tau phosphorylation in neurons remains unclear. Neurotrophin receptor p75 (p75(NTR)) is a receptor for A beta and mediates A beta neurotoxicity, implying that p75(NTR) may mediate A beta-induced tau phosphorylation in AD. Here, we showed that A beta-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-3 beta (GSK3 beta) significantly changed A beta/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 A beta to p75(NTR), suppressed tau hyperphosphorylation. Taken together, our findings suggest that p75(NTR) meditates A beta-induced tau pathology and is a potential druggable target for AD and other tauopathies.