Amelioration of Symptomatic Alzheimer’s Disease after Selective Impairment of p75 ^NTR Function in Adult Forebrain Excitatory Neurons

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 with 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.