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Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer's disease patients

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dc.contributor.author Pomilio, Carlos
dc.contributor.author Gorojod, Roxana M.
dc.contributor.author Riudavets, Miguel
dc.contributor.author Vinuesa, Ángeles
dc.contributor.author Presa, Jessica
dc.contributor.author Gregosa, Amal
dc.contributor.author Bentivegna, Melisa
dc.contributor.author Alaimo, Agustina
dc.contributor.author Porte Alcon, Soledad
dc.contributor.author Sevlever, Gustavo Emilio
dc.contributor.author Kotler, Mónica L.
dc.contributor.author Beauquis, Juan
dc.contributor.author Saravia, Flavia
dc.date.accessioned 2021-01-06T14:10:07Z
dc.date.available 2021-01-06T14:10:07Z
dc.date.issued 2020-01-23
dc.identifier.citation Pomilio, C., Gorojod, R.M., Riudavets, M., Vinuesa, A., Presa, J., Gregosa, A., Bentivegna, M., Alaimo, A., Alcon, S.P., Sevlever, G., Kotler, M.L., Beauquis, J., Saravia, F., 2020. Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer’s disease patients. Geroscience 42, 613–632. https://doi.org/10.1007/s11357-020-00161-9 en_US
dc.identifier.uri https://repositorio.fleni.org.ar/handle/123456789/295
dc.identifier.uri https://doi.org/10.1007/s11357-020-00161-9
dc.description.abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of misfolded proteins, amyloid-β (Aβ) aggregates, and neuroinflammation in the brain. Microglial cells are key players in the context of AD, being capable of releasing cytokines in response to Aβ and degrading aggregated proteins by mechanisms involving the ubiquitin-proteasome system and autophagy. Here, we present in vivo and in vitro evidence showing that microglial autophagy is affected during AD progression. PDAPPJ20 mice-murine model of AD-exhibited an accumulation of the autophagy receptor p62 and ubiquitin+ aggregates in Iba1+ microglial cells close to amyloid deposits in the hippocampus. Moreover, cultured microglial BV-2 cells showed an enhanced autophagic flux during a 2-h exposure to fibrillar Aβ, which was decreased if the exposure was prolonged to 24 h, a condition analogous to the chronic exposure to Aβ in the human pathology. The autophagic impairment was also associated with lysosomal damage, depicted by membrane permeabilization as shown by the presence of the acid hydrolase cathepsin-D in cytoplasm and altered LysoTracker staining. These results are compatible with microglial exhaustion caused by pro-inflammatory conditions and persistent exposure to aggregated Aβ peptides. In addition, we found LC3-positive autophagic vesicles accumulated in phagocytic CD68+ microglia in human AD brain samples, suggesting defective autophagy in microglia of AD brain. Our results indicate that the capacity of microglia to degrade Aβ and potentially other proteins through autophagy may be negatively affected as the disease progresses. Preserving autophagy in microglia thus emerges as a promising approach for treating AD. Graphical abstract. en_US
dc.language.iso eng en_US
dc.publisher Springer en_US
dc.rights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by/2.5/ar/
dc.subject Alzheimer Disease en_US
dc.subject Enfermedad de Alzheimer en_US
dc.subject Autophagy en_US
dc.subject Autofagia en_US
dc.subject Microglia en_US
dc.title Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer's disease patients en_US
dc.type info:eu-repo/semantics/publishedVersion
dc.type info:eu-repo/semantics/article en_US
dc.description.fil Fil: Sevlever, Gustavo Emilio. Fleni. Departamento de Neuropatología y Biología Molecular; Argentina.
dc.description.fil Fil: Riudavets, Miguel. Fleni. Departamento de Neuropatología y Biología Molecular; Argentina.
dc.description.fil Fil: Pomilio, Carlos. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Instituto de Biología y Medicina Experimental; Argentina.
dc.description.fil Fil: Gorojod, Roxana M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica; Argentina.
dc.description.fil Fil: Vinuesa, Ángeles. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Instituto de Biología y Medicina Experimental; Argentina.
dc.description.fil Fil: Presa, Jessica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Instituto de Biología y Medicina Experimental; Argentina.
dc.description.fil Fil: Gregosa, Amal. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Instituto de Biología y Medicina Experimental; Argentina.
dc.description.fil Fil: Bentivegna, Melisa. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Instituto de Biología y Medicina Experimental; Argentina.
dc.description.fil Fil: Alaimo, Agustina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires y Consejo Nacional de Investigaciones Científicas y Técnicas. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica; Argentina.
dc.description.fil Fil: Porte Alcon, Soledad. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica; Argentina.
dc.description.fil Fil: Kotler, Monica L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica; Argentina.
dc.description.fil Fil: Beauquis, Juan. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Instituto de Biología y Medicina Experimental; Argentina.
dc.description.fil Fil: Saravia, Flavia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Instituto de Biología y Medicina Experimental; Argentina.
dc.relation.ispartofVOLUME 42
dc.relation.ispartofNUMBER 2
dc.relation.ispartofPAGINATION 613-632
dc.relation.ispartofCOUNTRY Suiza
dc.relation.ispartofTITLE GeroScience
dc.relation.ispartofISSN 2509-2723
dc.type.snrd info:ar-repo/semantics/artículo es_ES


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