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

Xunde Xian, Theresa Pohlkamp, Murat S Durakoglugil, Connie H. Wong, Jürgen K. Beck, Courtney Lane-Donovan, Florian Plattner, Joachim Herz

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere40048
JournaleLife
Volume7
DOIs
StatePublished - Oct 1 2018

Fingerprint

Apolipoprotein E4
Recycling
Alzheimer Disease
Endosomes
Apolipoprotein E3
Low Density Lipoprotein Receptor-Related Protein-1
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Acidification
Isoelectric Point
Glutamate Receptors
N-Methylaspartate
Endocytosis
N-Methyl-D-Aspartate Receptors
Synapses
Protons
Rodentia
Protein Isoforms
Genotype
Modulation
Pharmacology

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease. / Xian, Xunde; Pohlkamp, Theresa; Durakoglugil, Murat S; Wong, Connie H.; Beck, Jürgen K.; Lane-Donovan, Courtney; Plattner, Florian; Herz, Joachim.

In: eLife, Vol. 7, e40048, 01.10.2018.

Research output: Contribution to journalArticle

Xian, Xunde ; Pohlkamp, Theresa ; Durakoglugil, Murat S ; Wong, Connie H. ; Beck, Jürgen K. ; Lane-Donovan, Courtney ; Plattner, Florian ; Herz, Joachim. / Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease. In: eLife. 2018 ; Vol. 7.
@article{c8460df293784c8ebaaabb57f1cede79,
title = "Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease",
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.",
author = "Xunde Xian and Theresa Pohlkamp and Durakoglugil, {Murat S} and Wong, {Connie H.} and Beck, {J{\"u}rgen K.} and Courtney Lane-Donovan and Florian Plattner and Joachim Herz",
year = "2018",
month = "10",
day = "1",
doi = "10.7554/eLife.40048",
language = "English (US)",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease

AU - Xian, Xunde

AU - Pohlkamp, Theresa

AU - Durakoglugil, Murat S

AU - Wong, Connie H.

AU - Beck, Jürgen K.

AU - Lane-Donovan, Courtney

AU - Plattner, Florian

AU - Herz, Joachim

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85057223909&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057223909&partnerID=8YFLogxK

U2 - 10.7554/eLife.40048

DO - 10.7554/eLife.40048

M3 - Article

VL - 7

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e40048

ER -