Inflammation, metabolism and glial cell activity in neurodegeneration

BEAUQUIS J; VINUESA A; GREGOSA A; BENTIVEGNA M; POMILIO C; BELLOTTO M; GONZALEZ PEREZ N; PRESA J; SARAVIA F

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2022

Sociedad Argentina de Investigación Clínica (SAIC)

The neurodegenerative process involves a series of cellular and molecular changes that eventually lead to neuronal dysfunction and death. It occurs in the course of neurological diseases like Alzheimer’s, metabolic diseases as Type 2 diabetes and obesity, and during the brain ageing process. Chronic inflammation, brain metabolic deficits and aberrant protein accumulation are common features in these scenarios. Glial cells could play a central role in the installment or the resolution of theses brain changes. In our laboratory we are interested in understanding how astrocytes and microglia respond to pathological stimuli to detect therapeutic opportunities. Glial cells could exacerbate or amplify the damage through the adoption of pro-inflammatory phenotypes and, also, through the loss of homeostatic and metabolic functions. Using models of insulin resistance and lipotoxicity, we detected brain and glial changes that are typically found in the neurodegenerative process. Fatty acid-induced inflammation leaded to microglial activation with NFkB nuclear translocation, increased IL1b expression, decreased IL4 expression, loss of phagocytic capacity and mitochondrial defects. Also, microglia amplified this response activating astrocytes through soluble factors and extracellular vesicles. This interaction was prevented with the pharmacological inhibition of ceramide synthesis, suggesting a role for this metabolic pathway. In parallel, using experimental models of Alzheimer’s disease, we have detected glial reactivity, impaired hippocampal insulin signaling and autophagic defects that could promote neurodegeneration. In vitro, the adoption of pro-inflammatory glial phenotypes was accompanied by autophagy deficiency, detected through the accumulation of p62+ and LC3+ intracellular vesicles. Also, astroglia displayed decreased Akt phosphorylation and lower levels of insulin receptors than control cells, suggesting impaired insulin signaling. Concomitant glial mitochondrial defects indicate a cellular metabolic deficiency. Finally, we found that dietary and pharmacological interventions could modulate some of these pathological changes. Altogether, our results suggest that glial reactivity and cellular metabolic changes are concurrent events in experimental models of neurodegeneration. We believe that these results would contribute to a better understanding of the pathophysiology of the neurodegenerative process and, ultimately, to design therapeutic approaches.