Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer's disease

Elife. 2018 Oct 30;7:e40048. doi: 10.7554/eLife.40048.

Abstract

ApoE4 genotype is the most prevalent and also clinically most important risk factor for late-onset Alzheimer's disease (AD). Available evidence suggests that the root cause for this increased risk is a trafficking defect at the level of the early endosome. ApoE4 differs from the most common ApoE3 isoform by a single amino acid that increases its isoelectric point and promotes unfolding of ApoE4 upon endosomal vesicle acidification. We found that pharmacological and genetic inhibition of NHE6, the primary proton leak channel in the early endosome, in rodents completely reverses the ApoE4-induced recycling block of the ApoE receptor Apoer2/Lrp8 and the AMPA- and NMDA-type glutamate receptors that are regulated by, and co-endocytosed in a complex with, Apoer2. Moreover, NHE6 inhibition restores the Reelin-mediated modulation of excitatory synapses that is impaired by ApoE4. Our findings suggest a novel potential approach for the prevention of late-onset AD.

Keywords: NHE; endosome; human; human biology; medicine; mouse; neurodegeneration; neuroscience; rat; recycling; synaptic plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / prevention & control*
  • Animals
  • Apolipoprotein E4 / genetics
  • Apolipoprotein E4 / metabolism*
  • Disease Models, Animal
  • Endosomes / metabolism*
  • Genotype
  • HEK293 Cells
  • Humans
  • LDL-Receptor Related Proteins / metabolism
  • Mice, Inbred C57BL
  • Rats, Sprague-Dawley
  • Receptors, Glutamate / metabolism
  • Sodium-Hydrogen Exchangers / antagonists & inhibitors*

Substances

  • Apolipoprotein E4
  • LDL-Receptor Related Proteins
  • NHE6 protein, mouse
  • Receptors, Glutamate
  • Sodium-Hydrogen Exchangers
  • low density lipoprotein receptor-related protein 8