1. Neuroscience
Download icon

Elevating acetyl-CoA levels reduces aspects of brain aging

  1. Antonio Currais  Is a corresponding author
  2. Ling Huang
  3. Joshua Goldberg
  4. Michael Petrascheck
  5. Gamze Ates
  6. António Pinto-Duarte
  7. Maxim N Shokhirev
  8. David Schubert
  9. Pamela Maher  Is a corresponding author
  1. The Salk Institute for Biological Studies, United States
  2. The Scripps Research Institute, United States
Research Article
  • Cited 34
  • Views 6,977
  • Annotations
Cite this article as: eLife 2019;8:e47866 doi: 10.7554/eLife.47866

Abstract

Because old age is the greatest risk factor for dementia, a successful therapy will require an understanding of the physiological changes that occur in the brain with aging. Here, two structurally distinct Alzheimer's disease (AD) drug candidates, CMS121 and J147, were used to identify a unique molecular pathway that is shared between the aging brain and AD. CMS121 and J147 reduced cognitive decline as well as metabolic and transcriptional markers of aging in the brain when administered to rapidly aging SAMP8 mice. Both compounds preserved mitochondrial homeostasis by regulating acetyl-coenzyme A (acetyl-CoA) metabolism. CMS121 and J147 increased the levels of acetyl-CoA in cell culture and mice via the inhibition of acetyl-CoA carboxylase 1 (ACC1), resulting in neuroprotection and increased acetylation of histone H3K9 in SAMP8 mice, a site linked to memory enhancement. These data show that targeting specific metabolic aspects of the aging brain could result in treatments for dementia.

Data availability

Whole transcriptomic data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE101112.

The following data sets were generated

Article and author information

Author details

  1. Antonio Currais

    Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    acurrais@salk.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4142-7054
  2. Ling Huang

    The Razavi Newman Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  3. Joshua Goldberg

    Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  4. Michael Petrascheck

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1010-145X
  5. Gamze Ates

    Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  6. António Pinto-Duarte

    Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2215-7653
  7. Maxim N Shokhirev

    The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  8. David Schubert

    Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    David Schubert, is an unpaid advisor for Abrexa Pharmaceuticals, a company working on the development of J147 for AD therapy. The Salk Institute holds the patents for CMS121 and J147.
  9. Pamela Maher

    Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    pmaher@salk.edu
    Competing interests
    No competing interests declared.

Funding

National Institutes of Health (R01 AG046153)

  • David Schubert
  • Pamela Maher

National Institutes of Health (RF1 AG054714)

  • David Schubert
  • Pamela Maher

Glenn Foundation for Medical Research

  • Joshua Goldberg

National Institutes of Health (R41 AI104034)

  • Pamela Maher

Edward N. and Della L. Thome Memorial Foundation

  • Pamela Maher

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were performed in accordance with the US Public Health Service Guide for Care and Use of Laboratory Animals and protocol 12-00001 approved by the IACUC at Salk Institute.

Reviewing Editor

  1. Agnieszka Chacinska, University of Warsaw, Poland

Publication history

  1. Received: April 23, 2019
  2. Accepted: November 18, 2019
  3. Accepted Manuscript published: November 19, 2019 (version 1)
  4. Version of Record published: November 28, 2019 (version 2)

Copyright

© 2019, Currais 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

  • 6,977
    Page views
  • 922
    Downloads
  • 34
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

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

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

Further reading

    1. Neuroscience
    Katherine B LeClair et al.
    Research Article

    Social hierarchy formation is strongly evolutionarily conserved. Across species, rank within social hierarchy has large effects on health and behavior. To investigate the relationship between social rank and stress susceptibility, we exposed ranked male and female mice to social and non-social stressors and manipulated social hierarchy position. We found that rank predicts same sex social stress outcomes: dominance in males and females confers resilience while subordination confers susceptibility. Pre-existing rank does not predict non-social stress outcomes in females and weakly does so in males, but rank emerging under stress conditions reveals social interaction deficits in male and female subordinates. Both history of winning and rank of cage mates affect stress susceptibility in males: rising to the top rank through high mobility confers resilience and mice that lose dominance lose stress resilience, though gaining dominance over a subordinate animal does not confer resilience. Overall, we have demonstrated a relationship between social status and stress susceptibility, particularly when taking into account individual history of winning and the overall hierarchy landscape in male and female mice.

    1. Cell Biology
    2. Neuroscience
    Zhong-Jiao Jiang et al.
    Research Article

    TRPM7 contributes to a variety of physiological and pathological processes in many tissues and cells. With a widespread distribution in the nervous system, TRPM7 is involved in animal behaviors and neuronal death induced by ischemia. However, the physiological role of TRPM7 in CNS neuron remains unclear. Here, we identify endocytic defects in neuroendocrine cells and neurons from TRPM7 knockout (KO) mice, indicating a role of TRPM7 in synaptic vesicle endocytosis. Our experiments further pinpoint the importance of TRPM7 as an ion channel in synaptic vesicle endocytosis. Ca2+ imaging detects a defect in presynaptic Ca2+ dynamics in TRPM7 KO neuron, suggesting an importance of Ca2+ influx via TRPM7 in synaptic vesicle endocytosis. Moreover, the short-term depression is enhanced in both excitatory and inhibitory synaptic transmission from TRPM7 KO mice. Taken together, our data suggests that Ca2+ influx via TRPM7 may be critical for short-term plasticity of synaptic strength by regulating synaptic vesicle endocytosis in neurons.