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

Ketotherapeutics 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.