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

Author:

Pohlkamp Theresa12ORCID,Xian Xunde123,Wong Connie H12ORCID,Durakoglugil Murat S12ORCID,Werthmann Gordon Chandler12,Saido Takaomi C4,Evers Bret M2ORCID,White Charles L5ORCID,Connor Jade12,Hammer Robert E6,Herz Joachim1278ORCID

Affiliation:

1. Department of Molecular Genetics, University of Texas Southwestern Medical Center

2. Center for Translational Neurodegeneration Research

3. Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University

4. Laboratory for Proteolytic Neuroscience, Riken Center for Brain Science

5. Pathology, University of Texas Southwestern Medical Center

6. Department of Biochemistry, University of Texas Southwestern Medical Center

7. Department of Neuroscience, University of Texas Southwestern Medical Center

8. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center

Abstract

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.

Funder

National Institutes of Health

BrightFocus Foundation

National Institute on Aging

Darrell K Royal Research Fund

Harrington Discovery Institute

Circle of Friends Pilot Synergy

Blue Field Project to Cure FTD

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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