Rejuvenation of senescent microglia using glucagon-like peptide-1 receptor agonist attenuates Alzheimer’s disease-like pathologies and behavioral deficits in aged 5xFAD mice model

Aging is associated with cellular senescence, wherein cells lose their replicative ability. Cellular senescence may contribute to various aging-related diseases, such as Alzheimer’s disease (AD). In this study, we investigated the therapeutic potential of glucagon-like peptide-1 receptor (GLP-1R) agonist in attenuating AD-like pathologies by targeting cellular senescence in microglia. Senescent microglia exhibited reduced GLP-1 secretion, increased senescence marker levels, and impaired phagocytic and metabolic functions. GLP-1R agonist treatment attenuated these conditions by reducing senescence markers and promoting microglial phagocytosis of amyloid-beta plaques. Furthermore, GLP-1R agonist treatment restored microglial function by enhancing oxidative phosphorylation and reducing lipid accumulation. In vivo GLP-1R agonist treatment showed improvements in cognitive function in 5xFAD mice, including spatial memory and novel object recognition, and decreased senescent microglia in the brain. Thus, GLP-1R agonists can be potential senotherapeutic agents for AD, which can be used to rejuvenate senescent microglia.