BETAHYDROXYBUTYRATE SUPPRESSES EPILEPTIFORM SPIKES AND IMPROVES COGNITION IN ALZHEIMER’S MOUSE MODEL

Abstract

Disruption of normal network activity and associated epileptiform spikes from dysfunctional inhibitory interneurons are important for the pathogenesis of cognitive decline in Alzheimer’s disease mouse models. Treatments that reduce epileptiform spikes improve cognition in these models and represent a promising new therapeutic approach for Alzheimer’s disease. Ketogenic diet and fasting have been used for centuries to treat certain forms of epilepsy, including those mechanistically related to disrupted network activity in Alzheimer’s models like Dravet syndrome. We found that ketogenic diet, but not fasting, consistently reduced epileptiform spikes in the APPJ20 Alzheimer’s mouse model. This reduction in spikes was independent or downstream of inhibitory interneuron function. The effect on spike reduction was sustained through several months of treatment. Long-term treatment resulted in cognitive improvement in the water maze and in habituation to the open field, and in the more severely affected male APPJ20 mice also improved survival. Finally, treatment with a novel compound that is metabolized to the ketone body beta-hydroxybutyrate immediately reduced epileptiform spikes in both APPJ20 and a model of Dravet syndrome to a similar degree as ketogenic diet. We suggest that therapies utilizing such ketomimetic agents, including agents that increase blood levels of beta-hydroxybutyrate or act on downstream targets of beta-hydroxybutyrate, may have therapeutic potential in Alzheimer’s disease through improving network function and ameliorating epileptiform activity.