NHE6-depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load

Abstract

Apolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimer's disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger 6 (NHE6) restores vesicular trafficking and normalizes synaptic homeostasis. Remarkably and unexpectedly, loss of NHE6 (encoded by the gene Slc9a6) in mice effectively suppressed amyloid deposition even in the absence of ApoE4, suggesting that accelerated acidification of early endosomes caused by the absence of NHE6 occludes the effect of ApoE on amyloid plaque formation. NHE6 suppression or inhibition may thus be a universal, ApoE-independent approach to prevent amyloid buildup in the brain. These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4 induced endolysosomal trafficking defect and reduces plaque load.

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All relevant data are included in the manuscript

Article and author information

Author details

  1. Theresa Pohlkamp

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3923-1917
  2. Xunde Xian

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    Xunde Xian, Inventor of Patent: https://patents.google.com/patent/US20110136832A1/en.
  3. Connie H Wong

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6452-7966
  4. Murat S Durakoglugil

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4483-8166
  5. Gordon Chandler Werthmann

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  6. Takaomi C Saido

    Laboratory for Proteolytic Neuroscience, Riken Center for Brain Science, Wako, Japan
    Competing interests
    No competing interests declared.
  7. Bret M Evers

    Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5686-0315
  8. Charles L White III

    Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3870-2804
  9. Jade Connor

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  10. Robert E Hammer

    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  11. Joachim Herz

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    joachim.herz@utsouthwestern.edu
    Competing interests
    Joachim Herz, Inventor of Patent: https://patents.google.com/patent/US20110136832A1/en.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8506-3400

Funding

National Institutes of Health

  • Joachim Herz

BrightFocus Foundation

  • Joachim Herz

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

Reviewing Editor

  1. Jeannie Chin, Baylor College of Medicine, United States

Ethics

Animal experimentation: All animal procedures were performed according to the approved guidelines (Animal Welfare Assurance Number D16-00296) for Institutional Animal Care and Use Committee (IACUC) at the University of Texas Southwestern Medical Center at Dallas.

Version history

  1. Preprint posted: March 23, 2021 (view preprint)
  2. Received: July 7, 2021
  3. Accepted: September 19, 2021
  4. Accepted Manuscript published: October 7, 2021 (version 1)
  5. Version of Record published: October 26, 2021 (version 2)

Copyright

© 2021, Pohlkamp 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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  1. Theresa Pohlkamp
  2. Xunde Xian
  3. Connie H Wong
  4. Murat S Durakoglugil
  5. Gordon Chandler Werthmann
  6. Takaomi C Saido
  7. Bret M Evers
  8. Charles L White III
  9. Jade Connor
  10. Robert E Hammer
  11. Joachim Herz
(2021)
NHE6-depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
eLife 10:e72034.
https://doi.org/10.7554/eLife.72034

Share this article

https://doi.org/10.7554/eLife.72034

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