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

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.

Reviewing Editor

  1. 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

  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.

Metrics

  • 48,547
    views
  • 4,457
    downloads
  • 88
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Karen Krukowski
  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
  12. Susanna Rosi
(2020)
Small molecule cognitive enhancer reverses age-related memory decline in mice
eLife 9:e62048.
https://doi.org/10.7554/eLife.62048

Share this article

https://doi.org/10.7554/eLife.62048

Further reading

    1. Neuroscience
    Alina Tetereva, Narun Pat
    Research Article

    One well-known biomarker candidate that supposedly helps capture fluid cognition is Brain Age, or a predicted value based on machine-learning models built to predict chronological age from brain MRI. To formally evaluate the utility of Brain Age for capturing fluid cognition, we built 26 age-prediction models for Brain Age based on different combinations of MRI modalities, using the Human Connectome Project in Aging (n=504, 36–100 years old). First, based on commonality analyses, we found a large overlap between Brain Age and chronological age: Brain Age could uniquely add only around 1.6% in explaining variation in fluid cognition over and above chronological age. Second, the age-prediction models that performed better at predicting chronological age did NOT necessarily create better Brain Age for capturing fluid cognition over and above chronological age. Instead, better-performing age-prediction models created Brain Age that overlapped larger with chronological age, up to around 29% out of 32%, in explaining fluid cognition. Third, Brain Age missed around 11% of the total variation in fluid cognition that could have been explained by the brain variation. That is, directly predicting fluid cognition from brain MRI data (instead of relying on Brain Age and chronological age) could lead to around a 1/3-time improvement of the total variation explained. Accordingly, we demonstrated the limited utility of Brain Age as a biomarker for fluid cognition and made some suggestions to ensure the utility of Brain Age in explaining fluid cognition and other phenotypes of interest.

    1. Developmental Biology
    2. Neuroscience
    Jonathan AC Menzies, André Maia Chagas ... Claudio R Alonso
    Research Article

    Movement is a key feature of animal systems, yet its embryonic origins are not fully understood. Here, we investigate the genetic basis underlying the embryonic onset of movement in Drosophila focusing on the role played by small non-coding RNAs (microRNAs, miRNAs). To this end, we first develop a quantitative behavioural pipeline capable of tracking embryonic movement in large populations of fly embryos, and using this system, discover that the Drosophila miRNA miR-2b-1 plays a role in the emergence of movement. Through the combination of spectral analysis of embryonic motor patterns, cell sorting and RNA in situs, genetic reconstitution tests, and neural optical imaging we define that miR-2b-1 influences the emergence of embryonic movement by exerting actions in the developing nervous system. Furthermore, through the combination of bioinformatics coupled to genetic manipulation of miRNA expression and phenocopy tests we identify a previously uncharacterised (but evolutionarily conserved) chloride channel encoding gene – which we term Movement Modulator (Motor) – as a genetic target that mechanistically links miR-2b-1 to the onset of movement. Cell-specific genetic reconstitution of miR-2b-1 expression in a null miRNA mutant background, followed by behavioural assays and target gene analyses, suggest that miR-2b-1 affects the emergence of movement through effects in sensory elements of the embryonic circuitry, rather than in the motor domain. Our work thus reports the first miRNA system capable of regulating embryonic movement, suggesting that other miRNAs are likely to play a role in this key developmental process in Drosophila as well as in other species.