TORC2: a novel target for treating age-associated memory impairment

Sci Rep. 2015 Oct 22;5:15193. doi: 10.1038/srep15193.

Abstract

Memory decline is one of the greatest health threats of the twenty-first century. Because of the widespread increase in life expectancy, 20 percent of the global population will be over 60 in 2050 and the problems caused by age-related memory loss will be dramatically aggravated. However, the molecular mechanisms underlying this inevitable process are not well understood. Here we show that the activity of the recently discovered mechanistic target of rapamycin (mTOR) complex 2 (mTORC2) declines with age in the brain of both fruit flies and rodents and that the loss of mTORC2-mediated actin polymerization contributes to age-associated memory loss. Intriguingly, treatment with a small molecule that activates mTORC2 (A-443654) reverses long-term memory (LTM) deficits in both aged mice and flies. In addition, we found that pharmacologically boosting either mTORC2 or actin polymerization enhances LTM. In contrast to the current approaches to enhance memory that have primarily targeted the regulation of gene expression (epigenetic, transcriptional, and translational), our data points to a novel, evolutionarily conserved mechanism for restoring memory that is dependent on structural plasticity. These insights into the molecular basis of age-related memory loss may hold promise for new treatments for cognitive disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / metabolism
  • Animals
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / physiology
  • Gene Expression Regulation / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Indazoles / administration & dosage
  • Indoles / administration & dosage
  • Mechanistic Target of Rapamycin Complex 2
  • Memory Disorders / genetics*
  • Memory Disorders / pathology
  • Memory Disorders / therapy
  • Memory, Long-Term / drug effects*
  • Memory, Long-Term / physiology
  • Mice
  • Multiprotein Complexes / genetics*
  • Multiprotein Complexes / therapeutic use
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics*
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / therapeutic use

Substances

  • A 443654
  • Actins
  • Indazoles
  • Indoles
  • Multiprotein Complexes
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2