Adeno-associated Virus Gene Therapy With Cholesterol 24-Hydroxylase Reduces the Amyloid Pathology Before or After the Onset of Amyloid Plaques in Mouse Models of Alzheimer's Disease
Adeno-associated Virus Gene Therapy With Cholesterol 24-Hydroxylase Reduces the Amyloid Pathology Before or After the Onset of Amyloid Plaques in Mouse Models of Alzheimer's Disease
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DOI：
10.1038/mt.2009.175
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发表时间：
2010-01-01
影响因子：
12.4
通讯作者：
Cartier, Nathalie
中科院分区：
文献类型：
--
作者：
Hudry, Eloise;Van Dam, Debby;Cartier, Nathalie
阿尔茨海默病（Alzheimer's disease，AD）的发生发展与胆固醇代谢密切相关。胆固醇增加淀粉样蛋白-β（A β）肽的产生和沉积，导致淀粉样蛋白斑块的形成，这是病理学的标志。在大脑中，胆固醇在原位合成，但不能降解，也不能穿过血脑屏障。脑胆固醇的主要输出形式是24 S-羟基胆固醇，这是一种由CYP 46 A1基因编码的神经元胆固醇24-羟化酶产生的氧化固醇。我们报告说，注射腺相关载体（AAV）编码CYP 46 A1在APP 23小鼠皮质和海马淀粉样蛋白沉积的发病前显着减少A β肽，淀粉样蛋白沉积和三聚体寡聚体在12个月大。Morris水迷宫（MWM）程序也显示在淀粉样蛋白沉积开始前的6个月时空间记忆改善。AAV 5-wtCYP 46 A1载体注射到淀粉样蛋白前体蛋白/早老素1（APP/PS）小鼠的皮质和海马中，在淀粉样蛋白沉积开始后3个月，也显著减少了海马中的淀粉样蛋白斑块的数量，并且在皮质中的程度较低。我们的数据表明，在小鼠AD模型中，在淀粉样斑块发生之前或之后，神经元CYP 46 A1过表达显著降低A β病理学。
The development of Alzheimer's disease (AD) is closely connected with cholesterol metabolism. Cholesterol increases the production and deposition of amyloid-beta (A beta) peptides that result in the formation of amyloid plaques, a hallmark of the pathology. In the brain, cholesterol is synthesized in situ but cannot be degraded nor cross the blood-brain barrier. The major exportable form of brain cholesterol is 24S-hydroxycholesterol, an oxysterol generated by the neuronal cholesterol 24-hydroxylase encoded by the CYP46A1 gene. We report that the injection of adeno-associated vector (AAV) encoding CYP46A1 in the cortex and hippocampus of APP23 mice before the onset of amyloid deposits markedly reduces A beta peptides, amyloid deposits and trimeric oligomers at 12 months of age. The Morris water maze (MWM) procedure also demonstrated improvement of spatial memory at 6 months, before the onset of amyloid deposits. AAV5-wtCYP46A1 vector injection in the cortex and hippocampus of amyloid precursor protein/presenilin 1 (APP/PS) mice after the onset of amyloid deposits also reduced markedly the number of amyloid plaques in the hippo-campus, and to a less extent in the cortex, 3 months after the injection. Our data demonstrate that neuronal overexpression of CYP46A1 before or after the onset of amyloid plaques significantly reduces A beta pathology in mouse models of AD.