Genetic Reduction of Mammalian Target of Rapamycin Ameliorates Alzheimer's Disease-Like Cognitive and Pathological Deficits by Restoring Hippocampal Gene Expression Signature
- 1Banner Sun Health Research Institute, Sun City, Arizona 85351,
- 2Department of Biological, Geological, and Environmental Sciences, University of Catania, 95125 Catania, Italy,
- 3Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy, and
- 4Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004
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Author contributions: S.O. designed research; A.C. and C.B. performed research; A.C., V.D.P., A.M., and S.O. analyzed data; S.O. wrote the paper.
Abstract
Elevated mammalian target of rapamycin (mTOR) signaling has been found in Alzheimer's disease (AD) patients and is linked to diabetes and aging, two known risk factors for AD. However, whether hyperactive mTOR plays a role in the cognitive deficits associated with AD remains elusive. Here, we genetically reduced mTOR signaling in the brains of Tg2576 mice, a widely used animal model of AD. We found that suppression of mTOR signaling reduced amyloid-β deposits and rescued memory deficits. Mechanistically, the reduction in mTOR signaling led to an increase in autophagy induction and restored the hippocampal gene expression signature of the Tg2576 mice to wild-type levels. Our results implicate hyperactive mTOR signaling as a previous unidentified signaling pathway underlying gene-expression dysregulation and cognitive deficits in AD. Furthermore, hyperactive mTOR signaling may represent a molecular pathway by which aging contributes to the development of AD.
- Received February 25, 2014.
- Revision received April 7, 2014.
- Accepted April 30, 2014.
- Copyright © 2014 the authors 0270-6474/14/347988-11$15.00/0
