Histone deacetylase inhibitor attenuates the effects of 27-hydroxycholesterol on the rat brain.

ABSTRACT

Hypercholesterolemia is a risk factor for Alzheimer's disease (AD). Plasma cholesterol does not pass the blood-brain barrier whereas its metabolite 27-hydroxycholesterol (27-OHC) can enter the brain. High 27-OHC in the brain has been suggested to mediate hypercholesterolemia-induced impairments of learning and memory through promoting amyloid-ß accumulation and facilitating synaptic disruption. In AD brains, the activity of histone deacetylase (HDAC) is elevated. Treating AD animals with HDAC inhibitors decreases amyloid-ß levels and synaptic damages, which leads to memory improvement. Whether HDAC activity is involved in the actions of 27-OHC is still uncertain. In this study, 4 weekly injections of 27-OHC/vehicle were given to rats followed by 3 daily injections of HDAC inhibitor trichostatin (TSA)/vehicle. The results of Morris water maze test reveal that all rats have intact spatial learning ability during the 5-d training phase. However, the behavioral performance during the probe trial was impaired by 27-OHC treatment, which was improved by adding TSA treatments. Furthermore, 27-OHC treatments reduced the hippocampal levels of acetylated histone H3, acetylated α tubulin, insulin-degrading enzyme and postsynaptic protein PSD-95, indicating that 27-OHC treatments may induce enhanced HDAC activity, decreased amyloid-ß clearance and synaptic disruption. All reduced levels returned to the basal levels by adding TSA treatments. These findings support our hypothesis that HDAC activity is enhanced following long-term exposure to excess 27-OHC.