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

eLife

Bret M Evers¹  Robert E Hammer²  Jade Connor³  Theresa Pohlkamp³  Murat S Durakoglugil³  Gordon Chandler Werthmann³  Connie H Wong³  Joachim Herz⁴  Xunde Xian⁵  Takaomi C Saido⁶  Charles L White⁷ 

[1] Center for Translational Neurodegeneration Research, Dallas, United States;Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States;Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States;Center for Translational Neurodegeneration Research, Dallas, United States;Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States;Center for Translational Neurodegeneration Research, Dallas, United States;Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States;Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, United States;Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States;Center for Translational Neurodegeneration Research, Dallas, United States;Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China;Laboratory for Proteolytic Neuroscience, Riken Center for Brain Science, Wako, Japan;Pathology, University of Texas Southwestern Medical Center, Dallas, United States;

关键词: ApoE;    Alzheimer's;    NHE6;    neurodegeneration;    endosome;    trafficking;    Mouse;   

DOI  :  10.7554/eLife.72034

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY