Knockout of p75 neurotrophin receptor attenuates the hyperphospnorylation of Tau in pR5 mouse model

p75 neurotrophin receptor (p75(NTR)) has been implicated in Alzheimer's disease (AD). However, whether p75(NTR) is involved in Tau hyperphosphorylation, one of the pathologies observed in AD, remains unclear. In our previous study, the extracellular domain of p75(NTR) blocked amyloid beta (A beta) toxicity and attenuated A beta-induced Tau hyperphosphorylation. Here we show that, in the absence of A beta, p75(NTR) regulates Tau phosphorylation in the transgenic mice with the P301L human Tau mutation (pR5). The knockout of p75(NTR) in pR5 mice attenuated the phosphorylation of human Tau. In addition, the elevated activity of kinases responsible for Tau phosphorylation including glycogen synthase kinase 3 beta; cyclin-dependent-kinase 5; and Rho-associated protein kinase was also inhibited when p75(NTR) is knocked out in pR5 mice at 9 months of age. The increased caspase-3 activity observed in pR5 mice was also abolished in the absence of p75(NTR). Our study also showed that p75(NTR) is required for A beta- and pro-brain derived neurotrophin factor (proBDNF)-induced Tau phosphorylation, in vitro. Overall, our data indicate that p75(NTR) is required for Tau phosphorylation, a key event in the formation of neurofibrillary tangles, another hallmark of AD. Thus, targeting p75(NTR) could reduce or prevent the pathologic hyperphosphorylation of Tau.