AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice.
AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice.
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DOI：
10.1038/mt.2009.44
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发表时间：
2009-05
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淀粉样β肽（Aβ）聚集是阿尔茨海默病（AD）发病机制的起始步骤。淀粉样斑块形成后，反应性小胶质细胞和星形胶质细胞在斑块周围积聚并引起神经炎症，其中脑趋化因子在胶质细胞积聚中起主要作用。我们先前已经表明，在表达瑞典淀粉样前体蛋白（APP）突变体的AD转基因小鼠模型中，脑中趋化因子CCL 2的转基因过表达导致小胶质细胞积累和弥漫性淀粉样斑块沉积增加。在这里，我们报告，腺相关病毒（AAV）血清型1和2杂交有效地提供7 ND基因，显性阴性CCL 2突变体，在剂量反应的方式和表达高达1000倍以上的重组CCL 2的量超过基础水平后，在脑中单次给药。AAV 1/2杂合病毒主要感染神经元，无神经炎症，表达持续时间至少6个月。在APP/早老素-1（APP/PS1）双基因小鼠中表达的7 ND可减少星形/小胶质细胞增生、β-淀粉样变性，包括抑制纤维状和寡聚体Aβ积聚，并改善空间学习。我们的数据支持AAV 1/2系统是一个有用的工具，中枢神经系统基因传递，和抑制CCL 2可能是一个治疗目标，为改善AD相关的神经炎症。
Accumulation of aggregated amyloid-β peptide (Aβ) has been studied as an initial step of Alzheimer’s disease (AD) pathogenesis. Following amyloid plaque formation, reactive microglia and astrocytes accumulate around the plaques and cause neuroinflammation, where brain chemokines play a major role for the glial accumulation. We have previously shown that transgenic over-expression of chemokine CCL2 in the brain resulted in increased microglial accumulation and diffuse amyloid plaque deposition in a transgenic mouse model of AD expressing Swedish amyloid precursor protein (APP) mutant. Here we report that adeno-associated virus (AAV) serotype 1 and 2 hybrid efficiently deliver 7ND gene, a dominant-negative CCL2 mutant, in dose-response manner and express up to 1000-fold higher amount of recombinant CCL2 over basal level after single administration in brain. AAV1/2 hybrid virus mainly infected neurons without neuroinflammation, and the expression is sustained at least 6-months period. 7ND expressed in APP/presenilin-1 (APP/PS1) bigenic mice reduced astro/microgliosis, beta-amyloidosis, including suppression of both fibrillar and oligomer Aβ accumulation, and improved spatial learning. Our data support that AAV1/2 system is a useful tool for CNS gene delivery, and suppression of CCL2 may be a therapeutic target for the amelioration of AD-related neuroinflammation.
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影响因子：
12.4
作者：
Carty, Niki C.;Nash, Kevin;Morgan, Dave
通讯作者：
Morgan, Dave
影响因子：
105.7
作者：
Etminan, M;Gill, S;Samii, A
通讯作者：
Samii, A
DOI：
10.1083/jcb.200705042
发表时间：
2007-08-27
期刊：
The Journal of cell biology
影响因子：
--
作者：
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通讯作者：
Shen Y
影响因子：
3.4
作者：
Calvo, CF;Yoshimura, T;Mallat, M
通讯作者：
Mallat, M
影响因子：
2.1
作者：
Galasko, Douglas R.;Graff-Radford, Neil;Koo, Edward H.
通讯作者：
Koo, Edward H.