title: Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature.
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.
authors.affiliation: Banner Sun Health Research Institute, Sun City, Arizona 85351, Department of Biological, Geological, and Environmental Sciences, University of Catania, 95125 Catania, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Caccamo
authors.affiliation: Department of Biological, Geological, and Environmental Sciences, University of Catania, 95125 Catania, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: De Pinto
authors.affiliation: Department of Biological, Geological, and Environmental Sciences, University of Catania, 95125 Catania, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Messina
authors.affiliation: Banner Sun Health Research Institute, Sun City, Arizona 85351, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy, and.
authors.forename: Caterina
authors.initials: C
authors.lastname: Branca
authors.affiliation: Banner Sun Health Research Institute, Sun City, Arizona 85351, Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004 oddo@email.arizona.edu.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D007166:Immunosuppressive Agents; D058570:TOR Serine-Threonine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Aβ; amyloid-β; autophagy; plaques; tangles; tau