β-hydroxybutyrate (β-OHB) has been shown to exert an anti-inflammatory activity. Apolipoprotein-E (ApoE) is strongly associated with atherosclerosis and Alzheimer’s disease (AD). This study aimed to explore the therapeutic effect of β-OHB in the brain and the aorta of high-fat diet (HFD)-fed ApoE-deficient mice. We found in Apo-E deficient mice that β-OHB attenuated lipid deposition in the choroid plexus (ChP) and decreased amyloid plaque in the substantia nigra pars compacta. We also found decreased CD68-positive macroglia infiltration of the ChP in β-OHB-treated ApoE-deficient mice. β-OHB treatment ameliorated IgG extravasation into the hippocampal region of the brain. In vitro study using ChP mice cell line revealed that β-OHB attenuated oxidized low-density lipoprotein-induced ApoE-specific differentially expressed inflammatory ChP genes. Treatment with β-OHB reduced aortic plaque formation without affecting blood lipid profiles and decreased serum production of resistin, a well-established risk factor for both AD and atherosclerosis. Thus, the current study suggests and describes the therapeutic potential of β-OHB for the treatment of AD and atherosclerosis.

Methamphetamine (METH) is a powerful addictive psychostimulant that gives rise to severe abusers worldwide. While many studies have reported on the neurotoxicity of METH, blood–brain barrier (BBB) dysfunction has recently attracted attention as an essential target in METH-induced pathological changes in the brain. However, its mechanism has not been fully understood. We found that METH increased paracellular permeability and decreased vascular integrity through FITC–dextran and trans-endothelial electrical resistance (TEER) assay in primary human brain endothelial cells (HBMECs). Also, redistribution of tight junction proteins (zonula occluden-1 and claudin-5) and reorganization of F-actin cytoskeleton were observed in METH-exposed HBMECs. To determine the mechanism of METH-induced BBB disruption, the RhoA/ROCK signaling pathway was examined in METH-treated HBMECs. METH-activated RhoA, followed by an increase in the phosphorylation of downstream effectors, myosin light chain (MLC) and cofilin, occurs in HBMECs. Pretreatment with ROCK inhibitors Y-27632 and fasudil reduced the METH-induced increase in phosphorylation of MLC and cofilin, preventing METH-induced redistribution of junction proteins and F-actin cytoskeletal reorganization. Moreover, METH-induced BBB leakage was alleviated by ROCK inhibitors in vitro and in vivo. Taken together, these results suggest that METH induces BBB dysfunction by activating the RhoA/ROCK signaling pathway, which results in the redistribution of junction proteins via F-actin cytoskeletal reorganization.