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 Cys 259 (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.