NHE6-depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
- University of Texas Southwestern Medical Center, United States
- Riken Center for Brain Science, Japan
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
Murat S Durakoglugil
Charles L White III
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
- 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
- Preprint posted: March 23, 2021 (view preprint)
- Received: July 7, 2021
- Accepted: September 19, 2021
- Accepted Manuscript published: October 7, 2021 (version 1)
- 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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NHE6-depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
eLife 10:e72034.
https://doi.org/10.7554/eLife.72034
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Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17–42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.
