Cited by 109Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsAutophagy in Disease and Therapy

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

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Pomilio, Carlos, Gorojod, Roxana M., Riudavets, Miguel, Vinuesa, Angeles, Presa, Jessica, Gregosa, Amal, Bentivegna, Melisa, Alaimo, Agustina +5 more·2020·GeroScience

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.

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Authors
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.
Affiliations
  • Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
  • Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (AR)
Corresponding author
Saravia, Flavia
Venue
GeroScience
Published
2020-01-23
Volume
42
Issue
2
Pages
613-632
ISSN
  • 2152-4041 (ISSN-L)
  • 2509-2715
  • 2509-2723
OpenAlex
W3002574430
Cited by
109
References
63
Citations by year
2026: 11 · 2025: 21 · 2024: 20 · 2023: 18 · 2022: 20 · 2021: 12 · 2020: 7
FWCI
5.52
Type
journal article
Language
en
Open access
Locations
  • GeroScience (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Conicet (submittedVersion, cc-by-nc-sa)
Funders
  • Agencia Nacional de Promoción Científica y Tecnológica (PICT 2014-1168, PICT-2016-1572, PICT-2016-1146)
  • Secretaria de Ciencia y Tecnica, Universidad de Buenos Aires (UBACYT)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
Alzheimer's disease, microglia, autophagy, amyloid-beta, p62, lysosomal damage, neuroinflammation, BV-2 cells, cathepsin D, autophagic flux, autophagy dysfunction
MeSH terms
Alzheimer Disease, Animals, Autophagy, Disease Models, Animal, Humans, Mice, Inbred C57BL, Amyloid beta-Peptides, Microglia, Mice

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