ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD
ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD
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DOI：
10.1073/pnas.0913828107
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发表时间：
2010-02-16
影响因子：
11.1
通讯作者：
Chang, Ta-Yuan
中科院分区：
文献类型：
--
作者：
Bryleva, Elena Y.;Rogers, Maximillian A.;Chang, Ta-Yuan
胆固醇代谢与几种神经退行性疾病的发病机制有关，包括淀粉样蛋白-β的异常积累，这是阿尔茨海默病（AD）的病理标志之一。酰基辅酶A：胆固醇酰基转移酶（ACAT 1和ACAT 2）是两种将游离胆固醇转化为胆固醇酯的酶。ACAT抑制剂最近已成为AD治疗的有前途的候选药物。然而，ACAT抑制剂如何在大脑中发挥作用迄今仍不清楚。在这里，我们表明，ACAT 1是小鼠大脑中的主要功能同工酶。在三重转基因（即，3XTg-AD）小鼠导致全长人APPswe及其蛋白水解片段减少超过60%，并改善认知缺陷。在4个月大时，A1-导致24-羟基胆固醇（24 SOH）含量增加32%，这是大脑中的主要氧化固醇。它还导致AD小鼠脑中HMG-CoA还原酶（HMGR）蛋白质含量降低65%，甾醇合成速率降低28%。在海马神经元中，A1-导致24 SOH合成速率增加;用24 SOH处理海马神经元细胞导致hAPP和HMGR蛋白水平迅速下降。提供了一个模型来解释我们的研究结果：在神经元中，A1-导致胆固醇和内质网中24 SOH含量的增加，这导致hAPP和HMGR蛋白含量的减少，并导致淀粉样病变的改善。我们的研究支持ACAT 1作为治疗某些形式AD的治疗靶点的潜力。
Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-beta, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1-) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1-causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1-causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1-causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.