<p>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.</p>