期刊
NATURE CELL BIOLOGY
卷 7, 期 11, 页码 1118-1123出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1313
关键词
-
类别
资金
- NINDS NIH HHS [RF1 NS041783, R01 NS041783] Funding Source: Medline
Amyloid beta peptide (A beta) has a key role in the pathological process of Alzheimer's disease ( AD), but the physiological function of A beta and of the amyloid precursor protein (APP) is unknown(1,2). Recently, it was shown that APP processing is sensitive to cholesterol and other lipids(3-10). Hydroxymethylglutaryl-CoA reductase (HMGR) and sphingomyelinases (SMases) are the main enzymes that regulate cholesterol biosynthesis and sphingomyelin (SM) levels, respectively. We show that control of cholesterol and SM metabolism involves APP processing. A beta 42 directly activates neutral SMase and downregulates SM levels, whereas A beta 40 reduces cholesterol de novo synthesis by inhibition of HMGR activity. This process strictly depends on gamma-secretase activity. In line with altered A beta 40/42 generation, pathological presenilin mutations result in increased cholesterol and decreased SM levels. Our results demonstrate a biological function for APP processing and also a functional basis for the link that has been observed between lipids and Alzheimer's disease (AD).
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据