@article{ac76e2f528c04948aad822bfa0d9d701,
title = "NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces Amyloid plaque load",
abstract = "Apolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimer{\textquoteright}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 EEs 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.",
author = "Theresa Pohlkamp and Xunde Xian and Wong, {Connie H.} and Durakoglugil, {Murat S.} and Werthmann, {Gordon Chandler} and Saido, {Takaomi C.} and Evers, {Bret M.} and White, {Charles L.} and Jade Connor and Hammer, {Robert E.} and Joachim Herz",
note = "Funding Information: This work was supported by NIH grants R37 HL063762, R01 NS093382, R01 NS108115, and RF1 AG053391 to JH and 1F31 AG067708-01 to CHW as well as funding from the Darrell K Royal Research Fund to MD. While this work was ongoing, JH was further supported by the Bright Focus Foundation (A20135245) and (A2016396S); Harrington Discovery Institute; and Circle of Friends Pilot Synergy Grant; and the Blue Field Project to Cure FTD. We are indebted Rebekah Hewitt, Barsha Subbha, Huichuan Reyna, Issac Rocha, Tamara Terrones, Emily Boyle, Alisa Gilloon, Travis Wolff, and Eric Hall for their excellent technical assistance. We thank Dr Yuan Yang for creating the NHE6-FLAG plasmid and the UTSW Whole Brain Microscopy Facility (WBMF) in the Department of Neurology and Neurotherapeutics for assistance with slide scanning. The WBMF is supported by the Texas Institute for Brain Injury and Repair (TIBIR). John Shelton and the UT Southwestern{\textquoteright}s Histopathology Core provided help with paraffin sectioning as well as H&E and Thioflavin S staining. We thank Wolfgang Scholz for providing EMD87580. Publisher Copyright: {\textcopyright} Pohlkamp et al.",
year = "2021",
month = oct,
doi = "10.7554/eLife.72034",
language = "English (US)",
volume = "10",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}