Dietary cholesterol and estrogen administration elevate brain apolipoprotein E in mice by different mechanisms

Apolipoprotein (apo) E plays an important role in the whole body cholesterol homeostasis. Recent studies suggest that it may also be involved in the local cholesterol transport in the brain, and influence the pathogenesis of Alzheimer's disease (AD) by interacting with the beta-amyloid protein and brain lipoprotein receptors. Since apoE expression is highest in the brain, next only to the liver and associated with the pathogenesis of AD, we hypothesized that dietary and hormonal intervention, known to regulate hepatic apoE expression may also regulate brain apoE and thereby influence local cholesterol transport. To test this hypothesis, groups of male C57BL mice were fed either regular rodent chow or high fat (HF) and high cholesterol enriched diet for 3 weeks. In a separate study, groups of male mice were administered pharmacological doses of 17-beta estradiol for 5 consecutive days and sacrificed on the 6th day. As expected, HF diet elevated liver apoE mRNA and apoE synthesis. Similar to liver, brain apoE mRNA and synthesis also increased, following HF feeding. Estradiol administration increased liver apoE synthesis without affecting apoE mRNA. Interestingly, estradiol administration also increased the brain apoE synthesis, but without altering the brain apoE mRNA. These studies suggested that dietary cholesterol and estrogen administration elevated the brain apoE by different mechanisms.