Reversal of ApoE4 induced recycling block as a novel prevention approach for Alzheimer's disease
- University of Texas Southwestern Medical Center, United States
- 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
Murat S Durakoglugil
Courtney Lane-Donovan
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).
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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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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