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

  1. Karen Krukowski  Is a corresponding author
  2. Amber Nolan
  3. Elma S Frias
  4. Morgane Boone
  5. Gonzalo Ureta
  6. Katherine Grue
  7. Maria-Serena Paladini
  8. Edward Elizarraras
  9. Luz Delgado
  10. Sebastian Bernales
  11. Peter Walter  Is a corresponding author
  12. Susanna Rosi  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Fundación Ciencia & Vida, Chile
  3. Howard Hughes Medical Institute, University of California, San Francisco, United States
Research Article
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Cite this article as: eLife 2020;9:e62048 doi: 10.7554/eLife.62048

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

  1. Karen Krukowski

    Department of Physical Therapy and Rehabilitation Science, Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, United States
    For correspondence
    karen.krukowski@ucsf.edu
    Competing interests
    No competing interests declared.

  2. Amber Nolan

    Brain and Spinal Injury Center, Department of Pathology,, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  3. Elma S Frias

    Brain and Spinal Injury Center, Department of Pathology,, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  4. Morgane Boone

    Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7807-5542

  5. Gonzalo Ureta

    Fundación Ciencia & Vida, Santiago, Chile
    Competing interests
    Gonzalo Ureta, Works at Fundacion Ciencia & Vida and receive partial funding from Praxis Biotech..

  6. Katherine Grue

    Department of Physical Therapy and Rehabilitation Science, Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  7. Maria-Serena Paladini

    Department of Physical Therapy and Rehabilitation Science, Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  8. Edward Elizarraras

    Department of Physical Therapy and Rehabilitation Science, Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  9. Luz Delgado

    Fundación Ciencia & Vida, Santiago, Chile
    Competing interests
    No competing interests declared.

  10. Sebastian Bernales

    Fundación Ciencia & Vida, Santiago, Chile
    Competing interests
    Sebastian Bernales, SB is an employee of Praxis Biotech..

  11. Peter Walter

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    For correspondence
    peter@walterlab.ucsf.edu
    Competing interests
    Peter Walter, P.W. is an inventor on U.S. Patent 9708247 held by the Regents of the University of California that describes ISRIB and its analogs. Rights to the invention have been licensed by UCSF to Calico. P.W. is a consultant for Praxis Biotech LLC and Black Belt TX Limited..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6849-708X

  12. Susanna Rosi

    Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, United States
    For correspondence
    susanna.rosi@ucsf.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9269-3638

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.

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).

Reviewing Editor

  1. Pankaj Kapahi, Buck Institute for Research on Aging, United States

Publication history

  1. Received: August 12, 2020
  2. Accepted: November 10, 2020
  3. Accepted Manuscript published: December 1, 2020 (version 1)
  4. 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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