Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature

Antonella Caccamo, Vito De Pinto, Angela Messina, Caterina Branca, Salvatore Oddo

Research output: Contribution to journalArticle

90 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7988-7998
Number of pages11
JournalJournal of Neuroscience
Volume34
Issue number23
DOIs
StatePublished - Jan 1 2014

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Keywords

  • Amyloid-β
  • Autophagy
  • Plaques
  • Tangles
  • Tau

ASJC Scopus subject areas

  • Neuroscience(all)

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