TORC2: a novel target for treating age-associated memory impairment.
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.
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.|Memory and Brain Research Center (MBRC), Baylor College of Medicine, Houston, TX 77030, USA.
Jennifer L
JL
Johnson
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.|Memory and Brain Research Center (MBRC), Baylor College of Medicine, Houston, TX 77030, USA.
Wei
W
Huang
Biology and Biochemistry Department, University of Houston, Houston, TX 77004, USA.|Biology of Behavior Institute, University of Houston, Houston, TX 77004, USA.
Gregg
G
Roman
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.|Memory and Brain Research Center (MBRC), Baylor College of Medicine, Houston, TX 77030, USA.
Mauro
M
Costa-Mattioli
D000199:Actins / Q000378:metabolism; D000818:Animals; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D000076225:Mechanistic Target of Rapamycin Complex 2; D008569:Memory Disorders / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D057567:Memory, Long-Term / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics* / Q000627:therapeutic use; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000627:therapeutic use
C504035:A 443654; D000199:Actins; D007191:Indazoles; D007211:Indoles; D046912:Multiprotein Complexes; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases