Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice.

Molecular Neurodegeneration
Raquel Larramona-ArcasRoser Masgrau

Abstract

The apolipoprotein E (APOE) gene exists in three isoforms in humans: APOE2, APOE3 and APOE4. APOE4 causes structural and functional alterations in normal brains, and is the strongest genetic risk factor of the sporadic form of Alzheimer's disease (LOAD). Research on APOE4 has mainly focused on the neuronal damage caused by defective cholesterol transport and exacerbated amyloid-β and Tau pathology. The impact of APOE4 on non-neuronal cell functions has been overlooked. Astrocytes, the main producers of ApoE in the healthy brain, are building blocks of neural circuits, and Ca2+ signaling is the basis of their excitability. Because APOE4 modifies membrane-lipid composition, and lipids regulate Ca2+ channels, we determined whether APOE4 dysregulates Ca2+signaling in astrocytes. Ca2+ signals were recorded in astrocytes in hippocampal slices from APOE3 and APOE4 gene targeted replacement male and female mice using Ca2+ imaging. Mechanistic analyses were performed in immortalized astrocytes. Ca2+ fluxes were examined with pharmacological tools and Ca2+ probes. APOE3 and APOE4 expression was manipulated with GFP-APOE vectors and APOE siRNA. Lipidomics of lysosomal and whole-membranes were also performed. We found potentiation of ATP-e...Continue Reading

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Citations

Nov 26, 2020·Cells·Maria Calvo-RodriguezBrian J Bacskai
Feb 10, 2021·Neurochemical Research·Marloes VerkerkeJinte Middeldorp
Jun 1, 2021·Journal of Alzheimer's Disease : JAD·Mirjana Babić LekoGoran Šimić
Jul 3, 2021·Frontiers in Aging Neuroscience·Sanghamitra Bandyopadhyay
Oct 9, 2021·Frontiers in Neuroscience·Sabine C KoningsGunnar K Gouras

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Methods Mentioned

BETA
transfection
electrophoresis
PCR
confocal microscopy
lipidation

Software Mentioned

ImarisCell
NIS
IMARIS
LinReg PCR
SIMCA
Image lab
MATLAB
DA
MetaFluor
Elements

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