Disorders of the Nervous System
Author: Nicolas Gabriel Gonzalez Perez | Email: nicolasggonzalezperez@gmail.com
Nicolas G Gonzalez Perez1°2°, Luciano Arcucci1°2°, Melina Bellotto1°2°, Melisa Bentivegna1°2°, Jessica Presa1°2°, Juan Beauquis1°2°, Carlos Pomilio1°2°, Flavia Saravia1°2°
1° Instituto de Biología y Medicina Experimental (IByME-CONICET)
2° Departamento de Quimica Biologica (DQB-FCEN-UBA)
The global population is ageing, which is expected to increase the prevalence of age-related pathologies such as Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2D). These diseases share an exacerbated neuroinflammatory response coordinated by microglial cells. In this context, some key cellular processes are affected: there is evidence of a dysfunctional autophagic flux. Treatment with metformin (MET) has been associated with attenuated microglial activation and restored autophagic flux in T2D models. Our aim is to evaluate the therapeutic potential of MET in experimental AD using mouse models and in vitro experiments. In 9-month-old male PDAPP-J20 mice carrying AD mutations treated with MET (320 mg/kg i.p. three times a week for three weeks), we found a reduction in anxiety phenotype, improvement in spatial memory (evaluated by Open field test and Barnes maze, respectively) and a decrease in amyloid pathology in the hippocampus compared to vehicle-treated group. AD mice showed decreased levels of the homeostatic microglial marker TMEM119, which was reversed when treated with MET. Furthermore, in microglial BV2 cells exposed to amyloid peptides in vitro (A, 0.05 µM for 24h), a blockade of autophagic flux was observed as measured by the autophagosome marker p62, that was restored by MET (0.2 mM for 1h). These results suggest that metformin may reestablish cognitive performance by promoting microglial proteostasis in experimental models of AD.