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

Autor:	Xian X; Department 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., Pohlkamp T; Department 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., Durakoglugil MS; Department 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., Wong CH; Department 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., Beck JK; Jkb Consult Inc SPRL, Brussels, Belgium., Lane-Donovan C; Department 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., Plattner F; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States.; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, United States., Herz J; Department 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 States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2018 Oct 30; Vol. 7. Date of Electronic Publication: 2018 Oct 30.
DOI:	10.7554/eLife.40048
Abstrakt:	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. Competing Interests: XX, TP, MD, CW, JB, CL, FP, JH No competing interests declared (© 2018, Xian et al.)
Databáze:	MEDLINE
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