Small molecule cognitive enhancer reverses age-related memory decline in mice
- University of California, San Francisco, United States
- Fundación Ciencia & Vida, Chile
- Howard Hughes Medical Institute, University of California, San Francisco, United States
Abstract
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Institute on Aging (F32AG054126)
- Karen Krukowski
National Institutes of Health (R01AG056770)
- Susanna Rosi
National Center for Advancing Translational Sciences (TL1 TR001871)
- Amber Nolan
National Institute of Neurological Disorders and Stroke (K08NS114170)
- Amber Nolan
Howard Hughes Medical Institute
- Peter Walter
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Pankaj Kapahi, Buck Institute for Research on Aging, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of California, San Francisco.(Protocol 170302).
Version history
- Received: August 12, 2020
- Accepted: November 10, 2020
- Accepted Manuscript published: December 1, 2020 (version 1)
- Version of Record published: December 7, 2020 (version 2)
Copyright
© 2020, Krukowski et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Small molecule cognitive enhancer reverses age-related memory decline in mice
eLife 9:e62048.
https://doi.org/10.7554/eLife.62048
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