Reversal of ApoE4 induced recycling block as a novel prevention approach for Alzheimer's disease

  1. Xunde Xian  Is a corresponding author
  2. Theresa Pohlkamp
  3. Murat S Durakoglugil
  4. Connie H Wong
  5. Jürgen K Beck
  6. Courtney Lane-Donovan
  7. Florian Plattner
  8. Joachim Herz  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. JKB sprl, Belgium

Abstract

ApoE4 genotype is the most prevalent and also clinically most important risk factor for late-onset Alzheimer's disease (AD). Available evidence suggests that the root cause for this increased risk is a trafficking defect at the level of the early endosome. ApoE4 differs from the most common ApoE3 isoform by a single amino acid that increases its isoelectric point and promotes unfolding of ApoE4 upon endosomal vesicle acidification. We found that pharmacological and genetic inhibition of NHE6, the primary proton leak channel in the early endosome, in rodents completely reverses the ApoE4 induced recycling block of the ApoE receptor Apoer2/Lrp8 and the AMPA- and NMDA-type glutamate receptors that are regulated by and co-endocytosed in a complex with Apoer2. Moreover, NHE6 inhibition restores the Reelin-mediated modulation of excitatory synapses that is impaired by ApoE4. Our findings suggest a novel potential approach for the prevention of late-onset AD.

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. Xunde Xian

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Xunde.xian@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3059-1254
  2. Theresa Pohlkamp

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Murat S Durakoglugil

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4483-8166
  4. Connie H Wong

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6452-7966
  5. Jürgen K Beck

    JKB sprl, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  6. Courtney Lane-Donovan

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9504-8346
  7. Florian Plattner

    Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3150-1866
  8. Joachim Herz

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    joachim.herz@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8506-3400

Funding

National Institutes of Health (R37 HL63762)

  • Joachim Herz

BrightFocus Foundation (A2016396S)

  • Joachim Herz

Bluefield Project

  • Joachim Herz

National Institutes of Health (R01 NS108115)

  • Joachim Herz

National Institutes of Health (R01 NS093382)

  • Joachim Herz

National Institutes of Health (RF1 AG053391)

  • Joachim Herz

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 experimental procedures were performed according to the approved guidelines for Institutional Animal Care and Use Committee (IACUC) at the University of Texas Southwestern Medical Center at Dallas (Approval Number: A3472-01).

Reviewing Editor

  1. Hugo J Bellen, Baylor College of Medicine, United States

Publication history

  1. Received: July 12, 2018
  2. Accepted: October 29, 2018
  3. Accepted Manuscript published: October 30, 2018 (version 1)
  4. Version of Record published: November 28, 2018 (version 2)

Copyright

© 2018, Xian 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. Xunde Xian
  2. Theresa Pohlkamp
  3. Murat S Durakoglugil
  4. Connie H Wong
  5. Jürgen K Beck
  6. Courtney Lane-Donovan
  7. Florian Plattner
  8. Joachim Herz
(2018)
Reversal of ApoE4 induced recycling block as a novel prevention approach for Alzheimer's disease
eLife 7:e40048.
https://doi.org/10.7554/eLife.40048

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    Funding: financial support for this work from a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research (GIG), an Ontario Graduate Scholarship (SS), a Restracomp Research Fellowship provided by the Hospital for Sick Children (SS), an Institutional Research Chair in Neuroinformatics (MD), as well as a Natural Sciences and Engineering Research Council CREATE grant (MD).