Microglia in the context of aging and Alzheimer's disease

FLAVIA EUGENIA SARAVIA

Congreso; Reunion de la Sociedad Chilena de Neurociencias; 2021

Sociedad Chilena de Neurociencias

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized by the presence of extracellular amyloid plaques that are mainly composed by Amyloid-β peptides (Aβ). Microglia-a specialized population of macrophages-like cells in the central nervous system- are regarded as immune sentinels able of orchestrating an effective inflammatory response. Microglial activation plays a crucial role in the clearance of Aβ, and microglial autophagy may also participate in this function. In this presentation I will share part of our results showing that microglial autophagy could be affected during progression of AD, employing in vivo and in vitro models of the disease. The hippocampus of aged PDAPPJ20 mice –a validated mice model of AD– showed hyper reactive Iba1+ cells around plaques. Compared with age matched controls, microglia in AD mice lost the lysosomal phagocytic marker CD68, and showed a significant accumulation of ubiquitinized proteins located inside autophagosomes as evidenced by co localization with p62. Experiments using BV2 microglial cells exposed to fibrillar Aβ allowed us to assess the impact of AD progression on microglial autophagy during a short (2h) or a long (24h) period of time. A short exposure promoted a significant increment in autophagic flux, evaluated by LC3 detection and using the lysosomal blocker Bafilomycin A1. When Aβ exposure was longer -a condition closer to a chronic disease like AD-, autophagic flux was impaired, suggesting an accumulation of autophagosomes, which was also verified by transfection with a plasmid carrying LC3-GFP-mCherry. In addition, the long exposition to Aβ caused a significant increment in the percentage of cells exhibiting membrane permeability to lysotracker staining, fact compatible with lysosomal dysfunction. Furthermore, I will show evidence about microglia detection on human brain tissue from post mortem AD patients, where we found that the microglial cells located near the amyloid deposits were also LC3+. Our findings from experimental models could be relevant to understand key aspects of the human disease.