Intramuscular delivery of p75NTR ectodomain by an AAV vector attenuates cognitive deficits and Alzheimer's disease-like pathologies in APP/PS1 transgenic mice
Date
2016
Authors
Wang, Q.H.
Wang, Y.R.
Zhang, T.
Jiao, S.S.
Liu, Y.H.
Zeng, F.
Li, J.
Yao, X.Q.
Zhou, H.D.
Zhou, X.F.
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Journal article
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Journal of Neurochemistry, 2016; 138(1):163-173
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Abstract
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.
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Data source: Supporting information, http://onlinelibrary.wiley.com/doi/10.1111/jnc.13616/epdf
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Copyright 2016 International Society for Neurochemistry