Grant: CIHR Fellowship

Previous work from our lab has found that special cholesterol transport vehicles within the brain may play an important part in preventing amyloid plaques. Important cholesterol sensors within the body called Liver-X-receptors (LXR) are able to influence cholesterol metabolism via targeting genes involved in cholesterol metabolism. These target genes include the ATP-binding Cassette (ABC) transporter specifically ABCA1 and apolipoprotein E (apoE). ABCA1 is located on the membrane of cells and functions by transporting molecules into and out of the cell. In regards to cholesterol homeostasis ABCA1 functions as a cholesterol removal pump. ApoE is a cholesterol-binding protein which in the periphery transports excess lipids/cholesterol to be removed from the body. Within the brain apoE has been shown to be beneficial in decreasing beta-amyloid which is the major component of the characteristic plaques found in AD. ABCA1 is a key regulator of apoE and influences the level of apoE lipidation within the brain. A highly lipidated apoE molecule is more beneficial in facilitating cholesterol transport and preventing plaques formation. The use of compounds that are known stimulants for these LXRs have been shown to be effective in treating mouse models of atheroscelerosis and Alzheimer's disease. The main objective of this project is to determine whether the use of LXR agonists are influenced by the presence or absence of ABCA1. This work may lead to a clearer understanding of the role of cholesterol transporters in AD, and highlight them as potential therapeutic targets.