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, disrupt...

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Bibliographic Details
Published in:eLife 2021-10, Vol.10
Main Authors: Pohlkamp, Theresa, Xian, Xunde, Wong, Connie H, Durakoglugil, Murat S, Werthmann, Gordon Chandler, Saido, Takaomi C, Evers, Bret M, White, 3rd, Charles L, Connor, Jade, Hammer, Robert E, Herz, Joachim
Format: Article
Language:English
Subjects:
Ablation
Acidification
Alzheimer's
Alzheimer's disease
Animals
ApoE
Apolipoprotein E
Apolipoprotein E4
Apolipoprotein E4 - genetics
Apolipoprotein E4 - metabolism
Apolipoproteins
endosome
Endosomes
Female
Fibroblasts
Homeostasis
Hydrogen
Ligands
Low Density Lipoprotein Receptor-Related Protein-1 - genetics
Low Density Lipoprotein Receptor-Related Protein-1 - metabolism
Male
Mice
Mice, Knockout
Na+/H+-exchanging ATPase
Neomycin
neurodegeneration
Neurodegenerative diseases
Neuroscience
NHE6
Peptides
Plaque, Amyloid - genetics
Proteins
Risk factors
Sodium-Hydrogen Exchangers - genetics
Sodium-Hydrogen Exchangers - metabolism
Stem cells
trafficking
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Summary: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 ) 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.72034