1. Neuroscience
Download icon

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

  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  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. Riken Center for Brain Science, Japan
Research Article
  • Cited 0
  • Views 302
  • Annotations
Cite this article as: eLife 2021;10:e72034 doi: 10.7554/eLife.72034

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.

Data availability

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.

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.

Reviewing Editor

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

Publication history

  1. Received: July 7, 2021
  2. Accepted: September 19, 2021
  3. Accepted Manuscript published: October 7, 2021 (version 1)

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.

Metrics

  • 302
    Page views
  • 67
    Downloads
  • 0
    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
    Roni O Maimon-Mor et al.
    Research Article Updated

    The study of artificial arms provides a unique opportunity to address long-standing questions on sensorimotor plasticity and development. Learning to use an artificial arm arguably depends on fundamental building blocks of body representation and would therefore be impacted by early life experience. We tested artificial arm motor-control in two adult populations with upper-limb deficiencies: a congenital group—individuals who were born with a partial arm, and an acquired group—who lost their arm following amputation in adulthood. Brain plasticity research teaches us that the earlier we train to acquire new skills (or use a new technology) the better we benefit from this practice as adults. Instead, we found that although the congenital group started using an artificial arm as toddlers, they produced increased error noise and directional errors when reaching to visual targets, relative to the acquired group who performed similarly to controls. However, the earlier an individual with a congenital limb difference was fitted with an artificial arm, the better their motor control was. Since we found no group differences when reaching without visual feedback, we suggest that the ability to perform efficient visual-based corrective movements is highly dependent on either biological or artificial arm experience at a very young age. Subsequently, opportunities for sensorimotor plasticity become more limited.

    1. Cell Biology
    2. Neuroscience
    Shahzad S Khan et al.
    Research Advance

    Activating LRRK2 mutations cause Parkinson's disease, and pathogenic LRRK2 kinase interferes with ciliogenesis. Previously, we showed that cholinergic interneurons of the dorsal striatum lose their cilia in R1441C LRRK2 mutant mice (Dhekne et al., 2018). Here, we show that cilia loss is seen as early as 10 weeks of age in these mice and also in two other mouse strains carrying the most common human G2019S LRRK2 mutation. Loss of the PPM1H phosphatase that is specific for LRRK2-phosphorylated Rab GTPases yields the same cilia loss phenotype seen in mice expressing pathogenic LRRK2 kinase, strongly supporting a connection between Rab GTPase phosphorylation and cilia loss. Moreover, astrocytes throughout the striatum show a ciliation defect in all LRRK2 and PPM1H mutant models examined. Hedgehog signaling requires cilia, and loss of cilia in LRRK2 mutant rodents correlates with dysregulation of Hedgehog signaling as monitored by in situ hybridization of Gli1 and Gdnf transcripts. Dopaminergic neurons of the substantia nigra secrete a Hedgehog signal that is sensed in the striatum to trigger neuroprotection; our data support a model in which LRRK2 and PPM1H mutant mice show altered responses to critical Hedgehog signals in the nigrostriatal pathway.