194-OR: Sexually Dimorphic Microglial Senescence and Inflammatory Mechanisms in Obesity and Prediabetes Induced Cognitive Impairment

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Introduction and Objective: Rates of metabolic stress (obesity, prediabetes, metabolic syndrome, and diabetes) are increasing worldwide. Metabolic stress increases the risk of cognitive impairment, including dementias, with age. Immune system dysregulation/inflammation, including senescence-related inflammation, are common etiologies of metabolic stress, aging, and cognitive impairment. In particular, the cGAS/STING pathway is implicated as a critical inflammatory mechanism. However, its role in promoting cognitive impairment under conditions of metabolic stress remains unclear. Methods: Wild-type and cGAS knock-out (KO) male and female mice were fed standard or high fat diet (HFD; n=10-14 mice/group) from 1-2yrs of age. Longitudinal metabolic (body weight, glucose tolerance) and cognitive (puzzle box) phenotyping was performed throughout the feeding period. At terminal, hippocampal single cell RNAseq was also performed. Results: HFD-feeding increased weight gain and glucose intolerance, particularly in females. With age, mice experienced age-associated weight loss and moderate reduction in glucose tolerance, which was blunted in cGAS KO animals. HFD and age also worsened cognition, with the largest impact seen in females (particularly cGAS KO females). After 1yr of feeding, hippocampal gene expression profiles showed a pro-inflammatory, neurodegenerative effect of HFD-feeding. Additionally, there were a high number of senescence cells in the hippocampus, which were primarily found to be microglia. Further, female cGAS KO mice had the largest increase in microglial senesce cell burden due to HFD feeding. Conclusion: Metabolic and cognitive profiles were negatively impacted by HFD feeding, with female cGAS KO mice disproportionately impacted. This was likely due, at least in part, to their high burden of microglial senescence. More work is required to fully understand how cGAS/STING mediates microglial inflammatory and senescence responses, particularly accounting for sex. Disclosure S. Elzinga: None. K. Guo: None. D.M. Rigan: None. S. Teener: None. J. Park: None. A.D. Carter: None. J.M. Hayes: None. J. Hur: None. E.L. Feldman: None. Funding National Institutes of Health (1K99AG071667-01A1)

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