AGING IS ASSOCIATED WITH MEMORY DECLINE, SYNAPTIC LOSS AND A REACTIVE PHENOTYPE OF ASTROCYTES

Brain aging triggers molecular changes that may lead to cognitive decline. Astrocytes are glial cells involved in synapse formation and plasticity during development and their dysfunctions are associated with aging-related diseases. However, little is known about the phenotype of these cells during aging. Here, we investigated the memory performance of aged mice and the astrocytes' morphological and molecular profiles in aging experimental models. We performed the Novel Object Recognition test (NOR) in young (2-5 months) and aged (18-24 months) C57BL/6 mice and evaluated the levels of synaptic proteins in their hippocampal tissue. Additionally, we used a model of astrocyte senescence, in which cultures were maintained for 30-35 days in vitro (DIV) (senescent astrocytes) or 7-10 DIV (control astrocytes) to investigate the molecular profile of astrocytes. We observed that aged mice displayed impaired recognition memory performance on the NOR and reduced hippocampal levels of synaptic proteins, synaptophysin and PSD-95, compared to young mice. The GFAP (glial fibrillary acidic protein) immunostaining revealed astrocyte hypertrophy in the dentate gyrus (DG) of aged mice, as observed by a 70% increase in GFAP intensity and area per cell compared with the young group. Moreover, aged astrocytes exhibited a 50% increment in the number and length of their processes compared to young astrocytes. Sholl analysis confirmed the age-dependent higher morphological complexity of DG astrocytes. Senescent astrocyte cultures also showed a reactive phenotype, as observed by increased levels of lipocalin 2, C3 and S100A10 compared to control cultures. Our findings suggest an age-associated cognitive and synaptic decline in mice, accompanied by changes in astrocytes phenotype that might contribute to the cellular dysfunctions observed in the aging brain. The protocols of this study were approved by the Research Ethics Committees of the UFRJ and the University Medical Center Utrecht.