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

POMILIO C; GONZALEZ PEREZ N; VINUESA A; BELLOTTO M; CALANDRI I; CRIVELLI L; BENTIVEGNA M; GREGOSA A; PRESA J; SEVLEVER G; BEAUQUIS J; SARAVIA F

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2022

Sociedad Argentina de Investigación Clínica (SAIC)

Alzheimer’s disease (AD) is the leading cause of dementiaand 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 pathologiesnegatively impact brain function, affecting cellularmetabolism and causing chronic neuroinflammation byactivating microglial cells, responsible for local immuneresponse. We and others reported in association withaging, AD and T2D, that neuroinflammation is linked toloss of proteostasis and altered cell metabolism in microglialcells, altogether termed as microglial dystrophy.During the last years, it was reported that metformin, thefirst-line drug used for T2D treatment, exhibits pleiotropiceffects on these alterations. So, this line of researchwas designed to characterize the cellular alterations relatedto 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 aggregationin 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 westerndiet. In both cases, we found an increased neuroinflammatoryresponse and microglial activation in associationwith decreased autophagic flux. In T2D mice, thiscondition also caused impaired spatial memory, and decreasedbrain 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 observationaland multicenter study ADNI also showed a bettercognitive performance in neuropsychological tests whenthey were treated with metformin compared to other antidiabeticdrugs. Considering diabetic patients diagnosedwith AD, metformin-treated patients showed a better cognitiveprofile, reduced pathological biomarkers for AD inCSF and reduced brain atrophy. Altogether these resultssuggest that metformin could be proposed as a potentialtherapeutic approach for brain dysfunction in AD andT2D, and that its mechanism of action could be partiallymediated by reversing microglial dystrophy.