Intramuscular delivery of p75NTR ectodomain by an AAV vector attenuates cognitive deficits and Alzheimer's disease-like pathologies in APP/PS1 transgenic mice
Intramuscular delivery of p75NTR ectodomain by an AAV vector attenuates cognitive deficits and Alzheimer's disease-like pathologies in APP/PS1 transgenic mice
复制标题
DOI：
10.1111/jnc.13616
复制
发表时间：
2016-07-01
影响因子：
4.7
通讯作者：
Wang, Yan-Jiang
中科院分区：
文献类型：
--
作者：
Wang, Qing-Hua;Wang, Ye-Ran;Wang, Yan-Jiang
神经营养因子受体p75（p75 NTR）是淀粉样蛋白β（A β）的受体，并介导A β诱导的神经退行性信号。p75 NTR的胞外域（p75 ECD）是阿尔茨海默病（Alzheimer's disease，AD）中抗Ab的生理保护因子。我们以前已经证明，从细胞表面脱落的p75 ECD是下调AD脑和脑中的p75 ECD水平的恢复，通过颅内给药的p75 ECD的腺相关病毒载体，减弱AD小鼠模型中的AD样病变。在本研究中，我们进一步研究了AAVp 75 ECD外周给药对脑淀粉样蛋白负荷和相关发病机制的可行性和有效性。我们发现，肌肉内递送AAV-p75 ECD增加血液中p75 ECD的水平，显著改善淀粉样前体蛋白/PS1转基因小鼠的行为表型，并减少脑淀粉样蛋白负荷，减弱Tau过度磷酸化和神经炎症。此外，肌肉内递送AAVp 75 ECD耐受良好。我们的研究结果表明，外周递送p75 ECD是一种安全有效的治疗AD的策略。
The neurotrophin receptor p75 (p75NTR) is a receptor for amyloid-beta (A beta) and mediates A beta-induced neurodegenerative signals. The ectodomain of p75NTR (p75ECD) is a physiological protective factor against Ab 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 adenoassociated 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 AAVp75ECD on brain amyloid burden and associated pathogen-esis. 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 AAVp75ECD was well tolerated. Our results indicate that peripheral delivery of p75ECD represents a safe and effective therapeutic strategy for AD.