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bioRxiv · 10.64898/2026.02.22.707328

p75 neurotrophin receptor signaling through the RhoA/ROCK pathway contributes to Alzheimers Disease tauopathy

Liao, K.·Xie, M.·Ibanez, C. F.
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Abstract

Therapeutic development in Alzheimers Disease (AD) has for the most part been focused on reducing {beta}-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 AD tauopathy, carrying mutant variants of the p75 neurotrophin receptor (p75NTR) deficient in RhoA/ROCK signaling are protected from neurodegeneration and cognitive impairment. Both p75{Delta}DD, lacking the death domain, and triple mutant p75KKEA, unable to interact with RhoGDI, decreased NFT levels, reduced gliosis, neurodegeneration and synapse loss, and improved spatial learning and memory in P301S mice. Intriguingly, p75C259A, 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{Delta}DD or p75KKEA, but not p75C259A, showed reduced phospho-Tau and ROCK and GSK3{beta} 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 p75NTR or p75C259A, but not p75{Delta}DD or p75KKEA. Together, these results indicate that p75NTR contributes to AD tauopathy by enhancing the activity of the RhoA-ROCK pathway.

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Liao, K., Xie, M., Ibanez, C. F.. 2026-02-23. p75 neurotrophin receptor signaling through the RhoA/ROCK pathway contributes to Alzheimers Disease tauopathy. https://doi.org/10.64898/2026.02.22.707328

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