p75 neurotrophin receptor signaling through the RhoA/ROCK pathway contributes to Tau-mediated neurodegeneration

Therapeutic development in Alzheimer’s Disease (AD) has for the most part been focused on reducing β-amyloid load. Nevertheless, neurofibrillary tangles (NFTs), produced by aggregation of hyper-phosphorylated Tau protein, correlate with neurodegeneration and cognitive impairment significantly better than amyloid accumulation in AD patients. Here we report that P301S mice, a model of Tau-mediated neurodegeneration, carrying mutant variants of the p75 neurotrophin receptor (p75 NTR ) deficient in RhoA/ROCK signaling are protected from neurodegeneration and cognitive impairment. Both p75 ∆DD , lacking the death domain, and triple mutant p75 KKEA , unable to interact with RhoGDI, decreased insoluble Tau species, reduced gliosis, neurodegeneration and synapse loss, and improved spatial learning and memory in P301S mice. Intriguingly, p75 C259A , a variant unresponsive to neurotrophins but still competent for RhoA signaling induced by myelin-derived ligands, did not afford any neuroprotection. P301S neurons expressing p75 ∆DD or p75 KKEA , but not p75 C259A , showed reduced phospho-Tau and ROCK and GSK3β activity, the two main kinases responsible for Tau phosphorylation. In line with this, treatment with myelin-associated glycoprotein (MAG) enhanced Tau phosphorylation and ROCK activity in P301S neurons expressing wild type p75 NTR or p75 C259A , but not p75 ∆DD or p75 KKEA . Together, these results indicate that p75 NTR contributes to AD Tauopathy by enhancing the activity of the RhoA-ROCK pathway.