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

Abstract

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 (Aβ) toxicity and attenuated Aβ-induced Tau hyperphosphorylation. Here we show that, in the absence of Aβ, 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 Aβ- and pro-brain derived neurotrophin factor (proBDNF)-induced Tau phosphorylation, <i>in vitro</i>. 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.