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Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice
Larramona-Arcas, Raquel (Universitat Autónoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
González-Arias, Candela (Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC))
Perea, Gertrudis (Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC))
Gutiérrez, Antonia (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED))
Vitorica, Javier (Universidad de Sevilla, Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia)
García-Barrera, Tamara (Universidad de Huelva. Departamento de Química, Facultad de Ciencias Experimentales, Campus de El Carmen, Centro de Investigación en Recursos Naturales, Salud y Medio Ambiente (RENSMA))
Gómez-Ariza, José Luis (Universidad de Huelva. Departamento de Química, Facultad de Ciencias Experimentales, Campus de El Carmen, Centro de Investigación en Recursos Naturales, Salud y Medio Ambiente (RENSMA))
Pascua-Maestro, Raquel (Instituto de Biología y Genética Molecular, Universidad de Valladolid-CSIC. Departamento de Bioquímica y Biología Molecular y Fisiología)
Ganfornina, María Dolores (Instituto de Biología y Genética Molecular, Universidad de Valladolid-CSIC. Departamento de Bioquímica y Biología Molecular y Fisiología)
Kara, Eleanna (Present Address: Institute of Neuropathology, University Hospital of Zurich)
Hudry, Eloise (Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129 USA)
Martinez-Vicente, Marta (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Vila Bover, Miquel (Universitat Autónoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Galea, Elena (Universitat Autónoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Masgrau, Roser (Universitat Autónoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date: 2020
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 Ca 2+ signaling is the basis of their excitability. Because APOE4 modifies membrane-lipid composition, and lipids regulate Ca 2+ channels, we determined whether APOE4 dysregulates Ca 2+ signaling in astrocytes. Ca 2+ signals were recorded in astrocytes in hippocampal slices from APOE3 and APOE4 gene targeted replacement male and female mice using Ca 2+ imaging. Mechanistic analyses were performed in immortalized astrocytes. Ca 2+ fluxes were examined with pharmacological tools and Ca 2+ 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-elicited Ca 2+ responses in APOE4 versus APOE3 astrocytes in male, but not female, mice. The immortalized astrocytes modeled the male response, and showed that Ca 2+ hyperactivity associated with APOE4 is caused by dysregulation of Ca 2+ 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 Ca 2+ fluxes by extracellular lipids, and present distinct lipid composition in lysosomal and plasma membranes. Immortalized APOE4 versus APOE3 astrocytes present: increased Ca 2+ excitability due to lysosome dysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation of Ca 2+ responses upon changes in extracellular lipids. Ca 2+ 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.
Note: Altres ajuts: This research was mainly funded by grants TV3-20141430, TV3-20141432 and TV3-20141431 from La Marató de Televisió de Catalunya (TV3) to EG, AG and JV respectively, co-financed by FEDER funds from European Union to AG. Co-financed by European Regional Development Fund to MDG.
Note: Número d'acord de subvenció AGAUR/2107 SGR1780
Note: Número d'acord de subvenció AGAUR/2017 SGR547
Note: Número d'acord de subvenció MINECO/ BFU2016-75107-P
Note: Número d'acord de subvenció MICINN/BFU2015-68149-R
Note: Número d'acord de subvenció ISCIII/PI18-01557
Note: Número d'acord de subvenció MINECO/BES-2017-080303
Rights: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Language: Anglès
Document: article ; recerca ; publishedVersion
Subject: APOE4 ; Astrocytes ; Calcium signaling ; Sex ; Lysosome ; Purinergic receptors ; Lipidome
Published in: Molecular neurodegeneration, Vol. 15 (june 2020) , ISSN 1750-1326

DOI: 10.1186/s13024-020-00382-8
PMID: 32517777


23 p, 4.3 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles

 Record created 2020-07-13, last modified 2021-01-12



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