The ACAT Inhibitor CP-113,818 Markedly Reduces Amyloid Pathology in a Mouse Model of Alzheimer's Disease
The ACAT Inhibitor CP-113,818 Markedly Reduces Amyloid Pathology in a Mouse Model of Alzheimer's Disease
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DOI：
10.1016/j.neuron.2010.11.028
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发表时间：
2010-12
期刊：
影响因子：
16.2
通讯作者：
B. Hutter-Paier;H. Huttunen;L. Puglielli;C. Eckman;Doo Yeon Kim;A. Hofmeister;R. Moir;Sarah B. Domnitz;M. Frosch;M. Windisch;D. Kovacs
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文献类型：
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作者：
B. Hutter-Paier;H. Huttunen;L. Puglielli;C. Eckman;Doo Yeon Kim;A. Hofmeister;R. Moir;Sarah B. Domnitz;M. Frosch;M. Windisch;D. Kovacs
β-淀粉样肽 (Aβ) 在特定大脑区域的积累是阿尔茨海默病 (AD) 的病理标志。我们之前曾报道过，一种经过充分表征的酰基辅酶 A：胆固醇酰基转移酶 (ACAT) 抑制剂 CP-113,818 可在细胞实验中抑制 Aβ 的产生。在这里，我们评估了 CP-113,818 在减少表达含有伦敦 (V717I) 和瑞典 (K670M/N671L) 突变的人 APP751 的转基因小鼠大脑中 AD 样病理的功效。使用 CP-113,818 治疗两个月，淀粉样斑块的积累减少了 88%–99%，膜/不溶性 Aβ 水平减少了 83%–96%，同时脑胆固醇酯也减少了 86%。此外，脑匀浆中的可溶性 Aβ42 减少了 34%。空间学习能力略有改善，并与 Aβ 水平降低相关。在非转基因同窝小鼠中，CP-113,818 还减少了大脑中内源 APP 的胞外域脱落。我们的结果表明，ACAT 抑制可能通过抑制 Aβ 肽的生成来有效预防和治疗 AD。
Amyloid β-peptide (Aβ) accumulation in specific brain regions is a pathological hallmark of Alzheimer's disease (AD). We have previously reported that a well-characterized acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, CP-113,818, inhibits Aβ production in cell-based experiments. Here, we assessed the efficacy of CP-113,818 in reducing AD-like pathology in the brains of transgenic mice expressing human APP751containing the London (V717I) and Swedish (K670M/N671L) mutations. Two months of treatment with CP-113,818 reduced the accumulation of amyloid plaques by 88%–99% and membrane/insoluble Aβ levels by 83%–96%, while also decreasing brain cholesteryl-esters by 86%. Additionally, soluble Aβ42was reduced by 34% in brain homogenates. Spatial learning was slightly improved and correlated with decreased Aβ levels. In nontransgenic littermates, CP-113,818 also reduced ectodomain shedding of endogenous APP in the brain. Our results suggest that ACAT inhibition may be effective in the prevention and treatment of AD by inhibiting generation of the Aβ peptide.