UC Davis

The Ketogenic diet (KD) extends mouse longevity and improves late-life memory. Blood betahydroxybutyrate(BHB) rises higher on ketogenic diets, which are extremely low on carbohydrates, compared to control diets (CD), which are rich in carbohydrates. BHB crosses the blood-brain barrier and is thought to underlie multiple KD benefits. We recently showed both the KD and BHB itself rescue memory in Alzheimer's PS1/APP mice. Here we investigated the concentration-dependence of BHB's anti-inflammatory effects in BV2 microglial cells. We focused on 1.5mM BHB for our studies, which is sustainably achieved in blood on the KD but not on the CD. 1.5mM BHB significantly and concentration-dependently suppressed phosphoextracellular signal-regulated kinase (p-ERK) and phospho-p38 mitogen-activated protein kinase (p-p38MAPK) signaling that underlie microglial inflammation, inflammatory cytokine expression (IL-6, TNF-α, IL-1β), and inflammatory circularity morphology. And for the first time we show 1.5mM BHB significantly and dose-dependently suppresses triggering receptor expressed on myeloid cells 2 (TREM2) gene expression; TREM2 mutations confer increased Alzheimer's disease (AD) risk. All of these BHB-dependent anti-inflammatory, morphological, biochemical, and TREM2 effects were blocked by a Monocarboxylate Transporter (MCT) inhibitor, suggesting BHB must enter the cell to elicit these anti-inflammatory effects. These results support a hypothesis that blood BHB levels physiologically and sustainably achievable on the KD, but not on the CD, elicit significant concentration-dependent anti-inflammatory effects in microglia. BHB's concentration-dependent effects suggest that increasing BHB concentration through sustained KD, or BHB supplements may lower microglial inflammatory tone and provide benefit in age related memory loss.