Canagliflozin as a Neuroprotective Agent to Improve Neuroinflammation and Cognitive Function during Aging

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ABSTRACT Aging is the dominant risk factor for most chronic diseases including neurodegenerative diseases. There is now ample evidence, in mice, that the process of aging can be delayed by pharmacological compounds that target numerous cellular and molecular pathways that have been implicated in the aging process and also delay multiple forms of late-life illness, including Alzheimer's disease (AD). In collaboration with the Intervention Testing Program (ITP), we have recently demonstrated that an FDA-approved anti-diabetes drug, Canagliflozin (Cana), a sodium- glucose transporter 2 (SGLT2) inhibitor, extended the lifespan in the genetically diverse UM-HET3 male mice by 14%, without an effect on females. The question of whether Cana has beneficial effects on the aging brain or amelioration of age-associated diseases in the brain remains open. Our new study demonstrated that Cana exhibits neuroprotective properties, such as improved central insulin responsiveness and reduced region-specific neuroinflammation. Furthermore, Cana treatment improved locomotor activity and exploratory behavior in aged male mice. Our preliminary data further reveal significant changes in hypothalamic transcriptome associated with decreased expression of genes related to activation of inflammatory responses specifically genes related to NLRP3 inflammasome activation in aged Cana-treated mice. Our central hypothesis is that Cana exhibits neuroprotective properties that may be applicable for the treatment of the aging brain and/or neurodegenerative diseases. This hypothesis will be assessed using genetically diverse UM-HET3 mice fed with Cana from 7 months of age and followed longitudinally by combining physiological, molecular, and genetic approaches. We will determine the effects of Cana treatment on cognitive function during aging and correlate this with the measurements of Cana levels in the brain. We will assess the Cana effect on microglia inflammasome activation and study brain spatial transcriptomic changes in aged mice to identify key pathways/genes mediating the pharmacological effects of Cana. Finally, we will determine the effects of Cana on cognitive performance using two well-established mice models of AD, 5xFAD and PS19 Tau. Our study has the potential to test the pharmacological effects of an established drug on cognitive degeneration in aging, as well as to identify novel cellular and molecular mechanisms underlying this pharmacological effect. Taken together, our study will validate Cana as a drug that can be rapidly used for preventing or treating AD in humans.