Microglial dystrophy during age-associated diseases: potential therapeutic role of metformin in Alzheimer?s disease and type 2 diabetes mellitus

CARLOS POMILIO; NICOLÁS GABRIEL GONZÁLEZ PÉREZ; ÁNGELES VINUESA; MELINA BELLOTTO; ISMAEL CALANDRI; LUCÍA CRIVELLI; MELISA BENTIVEGNA; AMAL GREGOSA; JESSICA PRESA; GUSTAVO SEVLEVER; JUAN BEAUQUIS; FLAVIA SARAVIA

Congreso; Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2022

Sociedad Argentina de Investigación Clínica

Alzheimer?s disease (AD) is the leading cause of de-entia and there is no effective cure available at day. Brain metabolism is early affected, and type 2 diabetes mellitus (T2D) is a strong risk factor for AD. Both pathologies negatively impact brain function, affecting cellular metabolism and causing chronic neuroinfammation byactivating microglial cells, responsible for local immune response. We and others reported in association with aging, AD and T2D, that neuroinfammation is linked to loss of proteostasis and altered cell metabolism in microglial cells, altogether termed as microglial dystrophy.During the last years, it was reported that metformin, the frst-line drug used for T2D treatment, exhibits pleiotropic effects on these alterations. So, this line of research was designed to characterize the cellular alterations related to dystrophy in microglial cells during AD and T2D and their potential reversion by metformin. Employing transgenic mice and cultured microglial cells as validated models for AD, we found increased activation, impaired autophagy, lysosomal dysfunction and protein aggregation in microglial cells from AD groups compared to controls. The impairment in autophagy was also evidenced in brain slices from AD patients. Microglial dystrophy was also evidenced in a mouse model of T2D by high-fat diet administration, and employing microglial cells exposed to palmitate, the main saturated fatty acid present in a western diet. In both cases, we found an increased neuroinfammatory response and microglial activation in association with decreased autophagic fux. In T2D mice, this condition also caused impaired spatial memory, and decreased brain insulin signaling compared to control mice.Interestingly, metformin administration in both in vivo and in vitro experimental models restored most of these alterations. Moreover, diabetic patients enrolled in the observational and multicenter study ADNI also showed a better cognitive performance in neuropsychological tests when they were treated with metformin compared to other antidiabetic drugs. Considering diabetic patients diagnosed with AD, metformin-treated patients showed a better cognitive profle, reduced pathological biomarkers for AD in CSF and reduced brain atrophy. Altogether these results suggest that metformin could be proposed as a potential therapeutic approach for brain dysfunction in AD and T2D, and that its mechanism of action could be partially mediated by reversing microglial dystrophy.