MICROGLIAL DYSTROPHY DURING AGE-ASSOCIATED DISEASES: POTENTIAL THERAPEUTIC ROLE OF METFORMIN IN ALZHEIMER’S DISEASE AND TYPE 2 DIABETES MELLITUS.

POMILIO, CARLOS; PÉREZ, NICOLÁS GONZÁLEZ; A VINUESA; BELLOTTO, MELINA; CALANDRI, ISMAEL; CRIVELI, LUCIA; GREGOSA, AMAL; PRESA, JESSICA; SEVLEVER, GUSTAVO; BEAUQUIS JUAN; FLAVIA EUGENIA SARAVIA

Mar del Plata

Congreso; Reunion Anual de la Sociedad Argentina de Investigacion Clinica; 2022

SAIC

Alzheimer’s disease (AD) is the leading cause of dementia and there is no effective cure available at day.Brain metabolism is early affected, and type 2 diabetesmellitus (T2D) is a strong risk factor for AD. Both pathologies negatively impact brain function, affecting cellularmetabolism and causing chronic neuroinfammation byactivating microglial cells, responsible for local immuneresponse. We and others reported in association withaging, AD and T2D, that neuroinfammation is linked toloss of proteostasis and altered cell metabolism in microglial cells, altogether termed as microglial dystrophy.During the last years, it was reported that metformin, thefrst-line drug used for T2D treatment, exhibits pleiotropic effects on these alterations. So, this line of researchwas designed to characterize the cellular alterations related to dystrophy in microglial cells during AD and T2Dand their potential reversion by metformin. Employingtransgenic mice and cultured microglial cells as validatedmodels for AD, we found increased activation, impairedautophagy, lysosomal dysfunction and protein aggregation in microglial cells from AD groups compared to controls. The impairment in autophagy was also evidencedin brain slices from AD patients. Microglial dystrophy wasalso evidenced in a mouse model of T2D by high-fat dietadministration, and employing microglial cells exposed topalmitate, 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, thiscondition also caused impaired spatial memory, and decreased brain insulin signaling compared to control mice.Interestingly, metformin administration in both in vivo andin vitro experimental models restored most of these alterations. Moreover, diabetic patients enrolled in the observational and multicenter study ADNI also showed a bettercognitive performance in neuropsychological tests whenthey were treated with metformin compared to other antidiabetic drugs. Considering diabetic patients diagnosedwith AD, metformin-treated patients showed a better cognitive profle, reduced pathological biomarkers for AD inCSF and reduced brain atrophy. Altogether these resultssuggest that metformin could be proposed as a potential therapeutic approach for brain dysfunction in AD andT2D, and that its mechanism of action could be partiallymediated by reversing microglial dystrophy