The acyl-coenzyme A: cholesterol acyltransferase inhibitor CI-1011 reverses diffuse brain amyloid pathology in aged amyloid precursor protein transgenic mice.
The acyl-coenzyme A: cholesterol acyltransferase inhibitor CI-1011 reverses diffuse brain amyloid pathology in aged amyloid precursor protein transgenic mice.
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DOI：
10.1097/nen.0b013e3181e77ed9
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发表时间：
2010-08
影响因子：
3.2
通讯作者：
Kovacs DM
中科院分区：
文献类型：
--
作者：
Huttunen HJ;Havas D;Peach C;Barren C;Duller S;Xia W;Frosch MP;Hutter-Paier B;Windisch M;Kovacs DM
淀粉样蛋白β多肽(Aβ)的脑积聚是阿尔茨海默病和淀粉样前体蛋白(APP)转基因小鼠的特征。在这里，我们评估了CI-1011，一种适合临床使用的酰基辅酶A：胆固醇酰基转移酶抑制剂，在减少年轻(6.5月龄)和老年(16月龄)HAPP转基因小鼠淀粉样蛋白病变方面的效果。用CI-1011治疗幼年动物可降低大脑皮质和海马区的淀粉样斑块负荷，并降低脑提取液中不溶性Aβ40和Aβ42以及APP的C末端片段的水平。在老年小鼠中，CI-1011特异性地减少弥漫性淀粉样斑块，而对硫代黄素S+致密核心斑块影响不大。弥漫性淀粉样蛋白的减少伴随着星形胶质细胞的抑制和小胶质细胞的激活。总而言之，这些数据表明，CI-1011治疗通过限制可扩散Aβ的生成和增加对可扩散A DNA的清除来减少HAPP小鼠的淀粉样蛋白负担。
Cerebral accumulation of amyloid β-peptide (Aβ) is characteristic of Alzheimer disease and of amyloid precursor protein (APP) transgenic mice. Here, we assessed the efficacy of CI-1011, an inhibitor of acyl-coenzyme A:cholesterol acyltransferase, which is suitable for clinical use, in reducing amyloid pathology in both young (6.5 months old) and aged (16 months old) hAPP transgenic mice. Treatment of young animals with CI-1011 decreased amyloid plaque load in the cortex and hippocampus and reduced the levels of insoluble Aβ40 and Aβ42 and C-terminal fragments of APP in brain extracts. In aged mice, CI-1011 specifically reduced diffuse amyloid plaques with a minor effect on thioflavin S+ dense-core plaques. Reduced diffusible amyloid was accompanied by suppression of astrogliosis and enhanced microglial activation. Collectively, these data suggest that CI-1011 treatment reduces amyloid burden in hAPP mice by limiting generation and increasing clearance of diffusible Aβ.