期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 17, 页码 13107-13120出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.100420
关键词
-
资金
- NIA [AG29729-4]
- San Antonio Nathan Shock Aging Center [1P30-AG-13319]
- Department of Veterans Affairs
Accumulation of amyloid-beta (A beta) and Tau is an invariant feature of Alzheimer disease (AD). The upstream role of A beta accumulation in the disease pathogenesis is widely accepted, and there is strong evidence showing that A beta accumulation causes cognitive impairments. However, the molecular mechanisms linking A beta to cognitive decline remain to be elucidated. Here we show that the buildup of A beta increases the mammalian target of rapamycin (mTOR) signaling, whereas decreasing mTOR signaling reduces A beta levels, thereby highlighting an interrelation between mTOR signaling and A beta. The mTOR pathway plays a central role in controlling protein homeostasis and hence, neuronal functions; indeed mTOR signaling regulates different forms of learning and memory. Using an animal model of AD, we show that pharmacologically restoring mTOR signaling with rapamycin rescues cognitive deficits and ameliorates A beta and Tau pathology by increasing autophagy. Indeed, we further show that autophagy induction is necessary for the rapamycin mediated reduction in A beta levels. The results presented here provide a molecular basis for the A beta-induced cognitive deficits and, moreover, show that rapamycin, an FDA approved drug, improves learning and memory and reduces A beta and Tau pathology.
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