@article{c8460df293784c8ebaaabb57f1cede79,
title = "Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer{\textquoteright}s disease",
abstract = "ApoE4 genotype is the most prevalent and also clinically most important risk factor for late-onset Alzheimer{\textquoteright}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.",
author = "Xunde Xian and Theresa Pohlkamp and Durakoglugil, {Murat S} and Wong, {Connie H.} and Beck, {J{\"u}rgen K.} and Courtney Lane-Donovan and Florian Plattner and Joachim Herz",
note = "Funding Information: Funder Grant reference number Author National Institutes of HealthR37 HL63762 Joachim Herz BrightFocus FoundationA2016396S Joachim Herz Bluefield Project Joachim Herz National Institutes of HealthR01 NS108115 Joachim Herz National Institutes of HealthR01 NS093382 Joachim Herz National Institutes of HealthRF1 AG053391 Joachim Herz The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding Information: This work was supported by NIH grant R37 HL63762, R01 NS093382, R01 NS108115, and RF1 AG053391 (to JH). While this work was conceived or ongoing, JH is or was further supported by the Alexander-von-Humboldt Foundation, the American Health Assistance Foundation, the Consortium for Frontotemporal Dementia Research, the Bright Focus Foundation, the Lupe Murchison Foundation, and The Ted Nash Long Life Foundation. The early stages of this work were partially supported by an unrestricted research grant from Merck KGaA. We are indebted to Rebekah Hewitt, Huichuan Reyna, Issac Rocha, Tamara Terrones, Emily Boyle, Alisa Gilloon, Travis Wolff, and Eric Hall for their excellent technical assistance, and Wolfgang Scholz and Dirk Beher for sharing reagents. Nancy Heard and Barbara Dacus for help with art work. Image acquisition was supported by NIH grant 1 S10 OD021685-01A1 to Kate Luby-Phelps. We also thank Charles White and the ADC at UT South-western for providing the pathology specimens first cited in (Durakoglugil et al., 2009), and Dr. Yuan Yang for performing several of the early experiments that were the basis for this paper. The sole reason why she is not included as a coauthor is that she has returned to China without leaving a contact address. Therefore, we were unable to provide the necessary assurance that she has read and approved the paper. She should be able to claim this publication as a coauthor and we would be delighted to add her as a third contributing author. Publisher Copyright: {\textcopyright} Xian et al.",
year = "2018",
month = oct,
doi = "10.7554/eLife.40048",
language = "English (US)",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}