Intramuscular delivery of p75 NTR ectodomain by an AAV vector attenuates cognitive deficits and Alzheimer's disease‐like pathologies in APP/PS 1 transgenic mice

Abstract

The neurotrophin receptor p75 (p75 NTR) is a receptor for amyloid‐beta (Aβ) and mediates Aβ‐induced neurodegenerative signals. The ectodomain of p75 NTR (p75 ECD) is a physiological protective factor against Aβ in Alzheimer's disease (AD). We have previously demonstrated that the shedding of p75 ECD from the cell surface is down‐regulated in AD brains and restoration of the p75 ECD level in the brain, through intracranial administration of p75 ECD by adeno‐associated virus vectors, attenuates AD‐like pathologies in an AD mouse model. In this study, we further investigated the feasibility and efficacy of peripheral administration of AAV‐p75 ECD on brain amyloid burden and associated pathogenesis. We found that intramuscular delivery of AAV‐p75 ECD increased the level of p75 ECD in the blood, significantly improved the behavioral phenotype of amyloid precursor protein/PS 1 transgenic mice, and reduced brain amyloid burden, attenuated Tau hyperphosphorylation, and neuroinflammation. Furthermore, intramuscular delivery of AAV‐p75 ECD was well tolerated. Our results indicate that peripheral delivery of p75 ECD represents a safe and effective therapeutic strategy for AD. image The ectodomain of p75NTR (p75ECD) is a physiological protective factor against amyloid‐beta (Aβ) in Alzheimer's disease (AD). Intramuscular delivery of AAV‐p75ECD increased the p75ECD levels in the blood, reduced brain amyloid burden through a ‘peripheral sink’ mechanism and alleviates AD‐type pathologies. Peripheral delivery of p75ECD represents a promising therapeutic strategy for AD.