Adeno-associated viral (AAV) serotype 5 vector mediated gene delivery of endothelin-converting enzyme reduces Aβ deposits in APP+PS1 transgenic mice
Adeno-associated viral (AAV) serotype 5 vector mediated gene delivery of endothelin-converting enzyme reduces Aβ deposits in APP+PS1 transgenic mice
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DOI：
10.1038/mt.2008.148
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发表时间：
2008-09-01
影响因子：
12.4
通讯作者：
Morgan, Dave
中科院分区：
文献类型：
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作者：
Carty, Niki C.;Nash, Kevin;Morgan, Dave
减少Aβ沉积是阿尔茨海默病（AD）的一种主要治疗策略。大脑中Aβ的浓度不仅受Aβ产生的调节，还受其降解的调节。参与Aβ肽降解的蛋白酶之一是内皮素转化酶（ECE）。在这项研究中，我们研究了颅内注射含有ECE - 1合成基因的血清型5重组腺相关病毒载体（rAAV）对淀粉样前体蛋白（APP）和早老素 - 1（PS1）转基因小鼠淀粉样沉积的影响。将rAAV载体单侧注射到6个月大小鼠的右侧前皮质和海马体中，而对照小鼠接受表达绿色荧光蛋白（GFP）的AAV载体。对附加在ECE上的血凝素（HA）标签进行的免疫组织化学检测显示，在注射部位周围区域有强烈表达，但在对侧区域表达极少。免疫组织化学检测表明，接受ECE合成基因的小鼠前皮质和海马体中的Aβ减少。此外，在这两个区域还观察到刚果红阳性沉积物的减少。这些结果表明，通过基因疗法增加β - 淀粉样蛋白降解酶的表达是治疗AD的一种有前途的方法。
Reduction of A beta deposition is a major therapeutic strategy in Alzheimer's disease (AD). The concentration of A beta in the brain is modulated not only by A beta production but also by its degradation. One of the proteases involved in the degradation of A beta peptides is endothelin-converting enzyme (ECE). In this study, we investigated the effects of an intracranial administration of a seroptype 5 recombinant adeno-associated viral vector (rAAV) containing the ECE-1 synthetic gene on amyloid deposition in amyloid precursor protein (APP) plus presenilin-1 (PS1) transgenic mice. The rAAV vector was injected unilaterally into the right anterior cortex and hippocampus of 6-month-old mice, while control mice received an AAV vector expressing green fluorescent protein (GFP). Immunohistochemical testing for the hemagglutinin (HA) tag appended to ECE revealed strong expression in areas surrounding the injection sites but minimal expression in the contralateral regions. Immunohistochemical tests showed that A beta decreases in the anterior cortex and hippocampus in mice receiving the ECE synthetic gene. Further, decreases in Congo red positive deposits were also observed in both regions. These results indicate that increasing the expression of beta-amyloid degrading enzymes through gene therapy is a promising approach to the treatment of AD.