The impact of mild episodic ketosis on microglia and hippocampal long‐term depression in 5xFAD mice

Abstract

AbstractKetotherapeutics is a potential metabolic intervention for mitigating dementias; however, its mechanisms and optimal methods of application are not well understood. Our previous in vitro study showed that β‐hydroxybutyrate (BHB), a major ketone body, reverses pathological features of amyloid‐β oligomer (AβO)‐activated microglia. Here we tested the in vivo effects of BHB on microglia and synaptic plasticity in the 5xFAD Alzheimer's disease (AD) mouse model. A short 1‐week regimen of daily intraperitoneal injection of BHB (250 mg/kg), which induced brief and mild daily episodic ketosis, was sufficient to mitigate pro‐inflammatory microglia activation and reduce brain amyloid‐β deposition by enhancing phagocytosis. Remarkably, it mitigated the deficits of hippocampal long‐term depression but not long‐term potentiation, and this effect was linked to suppression of NLRP3 inflammasome‐generated IL‐1β. As ketogenic diets are known for poor compliance, our study opens the possibility for alternative approaches such as short‐term BHB injections or dietary ketone esters that are less restrictive, potentially safer, and easier for compliance.