New paper reports amelioration of symptomatic Alzheimer’s Disease afterSelective Impairment of p75NTR function in adult forebrain excitatory neurons

The p75 neurotrophin receptor (p75 NTR ) contributes to the development of Alzheimer’s disease (AD) pathology by enhancing amy-loid precursor protein (APP) cleavage and amyloid plaque formation. However, the cell type-specific and temporal roles of p75NTR inAD progression remain unclear.

In this paper, 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 thosefound in whole-body knock-in mice. Strikingly, delaying introduction of p75NTR variants until advanced disease stages produced comparable beneficial effects and rescued behavior performance in cognitively impaired animals.

These findings suggest that blun-ing p75 NTR function can have beneficial effects even during symptomatic stages of AD, offering a potential therapeutic approachcomplementary to passive vaccination. 

The paper has been published in The Journal of Neuroscience