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

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 o...

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Autores principales: Pohlkamp, Theresa, Xian, Xunde, Wong, Connie H, Durakoglugil, Murat S, Werthmann, Gordon Chandler, Saido, Takaomi C, Evers, Bret M, White, Charles L, Connor, Jade, Hammer, Robert E, Herz, Joachim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547963/
https://www.ncbi.nlm.nih.gov/pubmed/34617884
http://dx.doi.org/10.7554/eLife.72034
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author Pohlkamp, Theresa
Xian, Xunde
Wong, Connie H
Durakoglugil, Murat S
Werthmann, Gordon Chandler
Saido, Takaomi C
Evers, Bret M
White, Charles L
Connor, Jade
Hammer, Robert E
Herz, Joachim
author_facet Pohlkamp, Theresa
Xian, Xunde
Wong, Connie H
Durakoglugil, Murat S
Werthmann, Gordon Chandler
Saido, Takaomi C
Evers, Bret M
White, Charles L
Connor, Jade
Hammer, Robert E
Herz, Joachim
author_sort Pohlkamp, Theresa
collection PubMed
description 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 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.
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spelling pubmed-85479632021-10-27 NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load Pohlkamp, Theresa Xian, Xunde Wong, Connie H Durakoglugil, Murat S Werthmann, Gordon Chandler Saido, Takaomi C Evers, Bret M White, Charles L Connor, Jade Hammer, Robert E Herz, Joachim eLife Neuroscience 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 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. eLife Sciences Publications, Ltd 2021-10-07 /pmc/articles/PMC8547963/ /pubmed/34617884 http://dx.doi.org/10.7554/eLife.72034 Text en © 2021, Pohlkamp et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Pohlkamp, Theresa
Xian, Xunde
Wong, Connie H
Durakoglugil, Murat S
Werthmann, Gordon Chandler
Saido, Takaomi C
Evers, Bret M
White, Charles L
Connor, Jade
Hammer, Robert E
Herz, Joachim
NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
title NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
title_full NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
title_fullStr NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
title_full_unstemmed NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
title_short NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
title_sort nhe6 depletion corrects apoe4-mediated synaptic impairments and reduces amyloid plaque load
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547963/
https://www.ncbi.nlm.nih.gov/pubmed/34617884
http://dx.doi.org/10.7554/eLife.72034
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