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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\n                    <jats:italic>Slc9a6<\/jats:italic>\n                    ) 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.\n                  <\/jats:p>","DOI":"10.7554\/elife.72034","type":"journal-article","created":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T08:05:06Z","timestamp":1633593906000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.72034","source":"Crossref","is-referenced-by-count":48,"title":["NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3923-1917","authenticated-orcid":true,"given":"Theresa","family":"Pohlkamp","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, University of Texas Southwestern Medical Center","place":["Dallas, United States"]},{"name":"Center for Translational Neurodegeneration Research","place":["Dallas, United 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