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J Neurochem. 2016 Jul;138(1):163-73. doi: 10.1111/jnc.13616. Epub 2016 Jun 6.

Intramuscular delivery of p75NTR ectodomain by an AAV vector attenuates cognitive deficits and Alzheimer's disease-like pathologies in APP/PS1 transgenic mice.

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Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
Division of Health Sciences, School of Pharmacy and Medical Sciences and Sansom Institute, University of South Australia, Adelaide, South Australia, Australia.


The neurotrophin receptor p75 (p75NTR) is a receptor for amyloid-beta (Aβ) and mediates Aβ-induced neurodegenerative signals. The ectodomain of p75NTR (p75ECD) is a physiological protective factor against Aβ in Alzheimer's disease (AD). We have previously demonstrated that the shedding of p75ECD from the cell surface is down-regulated in AD brains and restoration of the p75ECD level in the brain, through intracranial administration of p75ECD 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-p75ECD on brain amyloid burden and associated pathogenesis. We found that intramuscular delivery of AAV-p75ECD increased the level of p75ECD in the blood, significantly improved the behavioral phenotype of amyloid precursor protein/PS1 transgenic mice, and reduced brain amyloid burden, attenuated Tau hyperphosphorylation, and neuroinflammation. Furthermore, intramuscular delivery of AAV-p75ECD was well tolerated. Our results indicate that peripheral delivery of p75ECD represents a safe and effective therapeutic strategy for AD. 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.


Alzheimer's disease; amyloid-beta; ectodomain; gene therapy; intramuscular delivery; p75NTR

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