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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• 作者：Qing-Hua Wang ; Ye-Ran Wang ; Tao Zhang ; Shu-Sheng Jiao ; Yu-Hui Liu ; Fan Zeng ; Jing Li ; Xiu-Qing Yao ; Hua-Dong Zhou ; Xin-Fu Zhou and Yan-Jiang Wang
• 刊名：Journal of Neurochemistry
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：138
• 期：1
• 页码：163-173
• 全文大小：2653K
• ISSN：1471-4159

文摘

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.