Small molecule cognitive enhancer reverses age-related memory decline in mice

Elife. 2020 Dec 1:9:e62048. doi: 10.7554/eLife.62048.


With increased life expectancy, age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition (i) rescues intrinsic neuronal electrophysiological properties, (ii) restores spine density and (iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.

Keywords: ISR; aging; immune dysfunction; memory; mouse; neuroscience.

Publication types

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

MeSH terms

  • Acetamides / pharmacology*
  • Activating Transcription Factor 4 / metabolism
  • Aging / drug effects
  • Animals
  • Brain / drug effects
  • Cognitive Dysfunction / drug therapy
  • Cyclohexylamines / pharmacology*
  • Dendritic Spines / drug effects
  • Female
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Male
  • Memory / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Nootropic Agents / pharmacology*
  • Spatial Learning / drug effects
  • Stress, Physiological


  • 2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide
  • Acetamides
  • Atf4 protein, mouse
  • Cyclohexylamines
  • Nootropic Agents
  • Activating Transcription Factor 4