RT Journal Article
T1 Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice
A1 Larramona Arcas, Raquel
A1 González Arias, Candela
A1 Gómez Ariza, José Luis
A1 García Barrera, Tamara
AB 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 thesporadic form of Alzheimer’s disease (LOAD). Research on APOE4 has mainly focused on the neuronal damagecaused by defective cholesterol transport and exacerbated amyloid-β and Tau pathology. The impact of APOE4 onnon-neuronal cell functions has been overlooked. Astrocytes, the main producers of ApoE in the healthy brain, arebuilding blocks of neural circuits, and Ca2+ signaling is the basis of their excitability. Because APOE4 modifiesmembrane-lipid composition, and lipids regulate Ca2+ channels, we determined whether APOE4 dysregulatesCa2+signaling in astrocytes.Methods: Ca2+ signals were recorded in astrocytes in hippocampal slices from APOE3 and APOE4 gene targetedreplacement male and female mice using Ca2+ imaging. Mechanistic analyses were performed in immortalizedastrocytes. Ca2+ fluxes were examined with pharmacological tools and Ca2+ probes. APOE3 and APOE4 expressionwas manipulated with GFP-APOE vectors and APOE siRNA. Lipidomics of lysosomal and whole-membranes werealso performed.Results: We found potentiation of ATP-elicited Ca2+responses in APOE4 versus APOE3 astrocytes in male, but notfemale, mice. The immortalized astrocytes modeled the male response, and showed that Ca2+ hyperactivityassociated with APOE4 is caused by dysregulation of Ca2+ handling in lysosomal-enriched acidic stores, and isreversed 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 presentdistinct lipid composition in lysosomal and plasma membranes.Conclusions: Immortalized APOE4 versus APOE3 astrocytes present: increased Ca2+ excitability due to lysosomedysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation ofCa2+ responses upon changes in extracellular lipids. Ca2+ hyperactivity associated with APOE4 is found in astrocytesfrom male, but not female, targeted replacement mice. The study suggests that, independently of Aβ and Taupathologies, 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.
PB American Health Assistance Foundation
SN 1750-1326
YR 2020
FD 2020-06
LK http://hdl.handle.net/10272/18890
UL http://hdl.handle.net/10272/18890
LA eng
NO Larramona Arcas, R., González Arias, C., García Barrera, T. ...  Gómez Ariza, J. L. (2020). Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice. Molecular Neurodegeneration, 15(1). DOI: https://doi.org/10.1186/s13024-020-00382-8
NO This research was mainly funded by grants TV3–20141430, TV3–20141432and TV3–20141431 from La Marató de Televisió de Catalunya (TV3) to EG, AGand JV respectively, and grants 2107 SGR1780 from AGAUR (Generalitat deCatalunya) to RM, 2017 SGR547 from AGAUR (Generalitat de Catalunya) toEG, BFU2016–75107-P from Ministerio de Economia, Industria yCompetividad (Spanish Government) to GP, BFU2015–68149-R fromMinisterio de Ciencia e Innovación (Spanish Government) and co-financedby European Regional Development Fund to MDG and PI18/01557 fromInstituto de Salud Carlos III (ISCiii, Spanish Government) co-financed byFEDER funds from European Union to AG. CG-A was awarded a PhD fellow-ship BES-2017-080303 from Ministerio de Economía, Industria y Competivi-dad (Spanish Government).
DS Repositorio Institucional de la Universidad de Huelva
RD 1 jun 2026