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

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2020-06-09

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Larramona-Arcas, Raquel
González-Arias, Candela
Perea, Gertrudis
Gutiérrez, Antonia
Vitorica, Javier
García-Barrera, Tamara
Gómez-Ariza, José Luis
Pascua-Maestro, Raquel
Ganfornina, María Dolores
Kara, Eleanna

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BioMed Central, Springer Nature
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Background: 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. Methods: 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. Results: We found potentiation of ATP-elicited Ca2+responses in APOE4 versus APOE3 astrocytes in male, but not female, mice. The immortalized astrocytes modeled the male response, and showed that Ca2+ hyperactivity associated with APOE4 is caused by dysregulation of Ca2+ handling in lysosomal-enriched acidic stores, and is reversed by the expression of APOE3, but not of APOE4, pointing to loss of function due to APOE4 malfunction. Moreover, immortalized APOE4 astrocytes are refractory to control of Ca2+ fluxes by extracellular lipids, and present distinct lipid composition in lysosomal and plasma membranes. Conclusions: Immortalized APOE4 versus APOE3 astrocytes present: increased Ca2+ excitability due to lysosome dysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation of Ca2+ responses upon changes in extracellular lipids. Ca2+ hyperactivity associated with APOE4 is found in astrocytes from male, but not female, targeted replacement mice. The study suggests that, independently of Aβ and Tau pathologies, altered astrocyte excitability might contribute to neural-circuit hyperactivity depending on APOE allele, sex and lipids, and supports lysosome-targeted therapies to rescue APOE4 phenotypes in LOAD.

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Medical Subject Headings::Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Dementia::Alzheimer Disease
Medical Subject Headings::Organisms::Eukaryota::Animals
Medical Subject Headings::Chemicals and Drugs::Lipids::Lipoproteins::Apolipoproteins::Apolipoproteins E::Apolipoprotein E3
Medical Subject Headings::Chemicals and Drugs::Lipids::Lipoproteins::Apolipoproteins::Apolipoproteins E::Apolipoprotein E4
Medical Subject Headings::Anatomy::Nervous System::Neuroglia::Astrocytes
Medical Subject Headings::Chemicals and Drugs::Biological Factors::Blood Coagulation Factors::Calcium
Medical Subject Headings::Chemicals and Drugs::Lipids::Membrane Lipids::Sterols::Cholesterol
Medical Subject Headings::Check Tags::Female
Medical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain::Limbic System::Hippocampus
Medical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Cytoplasmic Vesicles::Lysosomes
Medical Subject Headings::Check Tags::Male
Medical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic
Medical Subject Headings::Anatomy::Nervous System::Neurons
Medical Subject Headings::Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::Sex

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APOE4, Astrocytes, Calcium signaling, Sex, Lysosome, Purinergic receptors, Lipidome, Apolipoproteína E4, Astrocitos, Señalización del calcio, Sexo, Lisosomas, Receptores purinérgicos, Lipidómica

Citation

Larramona-Arcas R, González-Arias C, Perea G, Gutiérrez A, Vitorica J, García-Barrera T, et al. Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice. Mol Neurodegener. 2020 Jun 9;15(1):35