J NEUROSCI | Amelioration of symptomatic Alzheimer’s Disease after selective impairment of p75NTR function in adult forebrain excitatory neurons ｜ Carlos Ibanez Lab

Abstract

The p75 neurotrophin receptor (p75^NTR) contributes to the development of Alzheimer’s Disease (AD) pathology by enhancing amyloid precursor protein (APP) cleavage and amyloid plaque formation. However, the cell type-specific and temporal roles of p75^NTR in AD progression remain unclear. Here, we report that conditional knock-in of functionally impaired p75^NTR variants lacking the death domain (ΔDD) or transmembrane Cys²⁵⁹ (C259A) specifically in forebrain excitatory neurons of male and female 5xFAD mice significantly attenuated multiple AD-associated pathologies, including amyloid plaque accumulation, gliosis, neurite dystrophy, as well as learning and memory deficits. Hippocampal amyloid plaque burden was reduced to levels comparable to those found in whole-body knock-in mice. Strikingly, delaying introduction of p75^NTR variants until advanced disease stages produced comparable beneficial effects, and rescued behavior performance in cognitively impaired animals. These findings suggest that blunting p75^NTR function can have beneficial effects even during symptomatic stages of AD, offering a potential therapeutic approach complementary to passive vaccination.

Significance Statement Inactivation of p75^NTR has been reported to show various degrees of neuroprotection in Aβ-based mouse models of AD. As p75^NTR is expressed in several different cell types in the brain, it has been unclear whether the beneficial effects afforded arose from all cell types or only one. For therapeutic approaches to be viable in AD patients, any form of interference with its activity needs to demonstrate beneficial effects during symptomatic stages of the disease. Here, we show that replacement of native p75^NTR with signaling-impaired variants in forebrain excitatory neurons is sufficient to significantly alleviate neuropathological and behavioral outcomes in 5xFAD mice. Moreover, significant amelioration of neuropathology and cognitive deficits were achieved after acute disruption of p75^NTR during symptomatic AD stages.

DOI: https://www.jneurosci.org/content/early/2026/01/20/JNEUROSCI.1939-25.2026