Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau: Effects on cognitive impairments

Antonella Caccamo, Smita Majumder, Arlan Richardson, Randy Strong, Salvatore - Oddo

Research output: Contribution to journalArticle

491 Citations (Scopus)

Abstract

Accumulation of amyloid-β (Aβ) and Tau is an invariant feature of Alzheimer disease (AD). The upstream role of Aβ accumulation in the disease pathogenesis is widely accepted, and there is strong evidence showing that Aβ accumulation causes cognitive impairments. However, the molecular mechanisms linking Aβ to cognitive decline remain to be elucidated. Here we show that the buildup of Aβ increases the mammalian target of rapamycin (mTOR) signaling, whereas decreasing mTOR signaling reduces Aβ levels, thereby highlighting an interrelation between mTOR signaling and Aβ. 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 Aβ and Tau pathology by increasing autophagy. Indeed, we further show that autophagy induction is necessary for the rapamycin-mediated reduction in Aβ levels. The results presented here provide a molecular basis for the Aβ-induced cognitive deficits and, moreover, show that rapamycin, an FDA approved drug, improves learning and memory and reduces Aβ and Tau pathology.

Original languageEnglish (US)
Pages (from-to)13107-13120
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number17
DOIs
StatePublished - Apr 23 2010
Externally publishedYes

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Sirolimus
Amyloid
Autophagy
Pathology
Alzheimer Disease
Learning
Cognitive Dysfunction
Data storage equipment
Animals
Homeostasis
Animal Models

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau : Effects on cognitive impairments. / Caccamo, Antonella; Majumder, Smita; Richardson, Arlan; Strong, Randy; Oddo, Salvatore -.

In: Journal of Biological Chemistry, Vol. 285, No. 17, 23.04.2010, p. 13107-13120.

Research output: Contribution to journalArticle

Caccamo, Antonella ; Majumder, Smita ; Richardson, Arlan ; Strong, Randy ; Oddo, Salvatore -. / Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau : Effects on cognitive impairments. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 17. pp. 13107-13120.
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