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

POMILIO, CARLOS; GOROJOD, ROXANA M.; RIUDAVETS, MIGUEL; VINUESA, ANGELES; PRESA, JESSICA; GREGOSA, AMAL; BENTIVEGNA, MELISA; ALAIMO, AGUSTINA; ALCON, SOLEDAD PORTE; KOTLER, MONICA L.; BEAUQUIS, JUAN; SARAVIA, FLAVIA

GeroScience

Springer

Lugar: Lausanne; Año: 2020 vol. 42 p. 613 - 632

2509-2715

Alzheimer?s disease (AD) is a progressiveneurodegenerative disorder characterized by the presenceof misfolded proteins, amyloid-β (Aβ) aggregates,and neuroinflammation in the brain. Microglial cells arekey players in the context of AD, being capable ofreleasing cytokines in response to Aβ and degradingaggregated proteins by mechanisms involving theubiquitin-proteasome system and autophagy. Here, wepresent in vivo and in vitro evidence showing thatmicroglial autophagy is affected duringADprogression.PDAPPJ20 mice?murine model of AD?exhibited anaccumulation of the autophagy receptor p62 and ubiquitin+aggregates in Iba1+ microglial cells close toamyloid deposits in the hippocampus. Moreover, culturedmicroglial BV-2 cells showed an enhanced autophagicflux during a 2-h exposure to fibrillar Aβ,which was decreased if the exposure was prolonged to24 h, a condition analogous to the chronic exposure toAβ in the human pathology. The autophagic impairmentwas also associated with lysosomal damage, depicted bymembrane permeabilization as shown by the presenceof the acid hydrolase cathepsin-D in cytoplasm andaltered LysoTracker staining. These results are compatiblewith microglial exhaustion caused by proinflammatoryconditions and persistent exposure to aggregatedAβ peptides. In addition, we found LC3-positive autophagic vesicles accumulated in phagocyticCD68+ microglia in human AD brain samples, suggestingdefective autophagy in microglia of AD brain. Ourresults indicate that the capacity of microglia to degradeAβ and potentially other proteins through autophagymay be negatively affected as the disease progresses.Preserving autophagy in microglia thus emerges as apromising approach for treating AD.