Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease
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 is...
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doaj-56ac5602a3b543ba97edca746b7d6a702021-05-05T16:15:23ZengeLife Sciences Publications LtdeLife2050-084X2018-10-01710.7554/eLife.40048Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s diseaseXunde Xian0https://orcid.org/0000-0003-3059-1254Theresa Pohlkamp1Murat S Durakoglugil2https://orcid.org/0000-0003-4483-8166Connie H Wong3https://orcid.org/0000-0002-6452-7966Jürgen K Beck4Courtney Lane-Donovan5https://orcid.org/0000-0001-9504-8346Florian Plattner6https://orcid.org/0000-0002-3150-1866Joachim Herz7https://orcid.org/0000-0002-8506-3400Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United StatesJkb Consult Inc SPRL, Brussels, BelgiumDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United StatesCenter for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, 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 StatesApoE4 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.https://elifesciences.org/articles/40048neurodegenerationsynaptic plasticityendosomerecyclingNHE |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xunde Xian Theresa Pohlkamp Murat S Durakoglugil Connie H Wong Jürgen K Beck Courtney Lane-Donovan Florian Plattner Joachim Herz |
spellingShingle |
Xunde Xian Theresa Pohlkamp Murat S Durakoglugil Connie H Wong Jürgen K Beck Courtney Lane-Donovan Florian Plattner Joachim Herz Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease eLife neurodegeneration synaptic plasticity endosome recycling NHE |
author_facet |
Xunde Xian Theresa Pohlkamp Murat S Durakoglugil Connie H Wong Jürgen K Beck Courtney Lane-Donovan Florian Plattner Joachim Herz |
author_sort |
Xunde Xian |
title |
Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease |
title_short |
Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease |
title_full |
Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease |
title_fullStr |
Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease |
title_full_unstemmed |
Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease |
title_sort |
reversal of apoe4-induced recycling block as a novel prevention approach for alzheimer’s disease |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2018-10-01 |
description |
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. |
topic |
neurodegeneration synaptic plasticity endosome recycling NHE |
url |
https://elifesciences.org/articles/40048 |
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