Effect of DREAM inhibition on aging and neurodegeneration

Aging, both physiological and pathological, results in a widespread decline in cognitive, sensory, and motor functions. Adult hippocampal neurogenesis is a phenomenon that diminishes with age across various mammalian species and has been proposed as a significant factor linked to age-related cognitive deficits. Our laboratory's preliminary studies reveal that mice lacking the DREAM protein (dream -/-) exhibit cognitive improvement with aging, along with increased neurogenesis and greater development of immature neurons positive for DCX compared to wild-type mice of the same age. To further understand this phenotype, behavioral tests were conducted on dream -/- mice of different ages, as well as wild-type mice treated with repaglinide (RPG), an orally administered DREAM inhibitor. Subsequently, mice were sacrificed, and their hippocampi were submitted to immunohistological staining and RT-PCR gene expresión analysis. Our findings demonstrate that both genetic and pharmacological blockade of DREAM delays the onset of neurodegeneration in old mice and Alzheimer's disease models. Moreover, both dream -/- mice and RPG-treated mice show differences in astrocyte and microglial populations, at both histological and molecular levels. These glial alterations may be related with the cognitive improvements and the increase in hippocampal adult neurogenesis that we have previously observed.