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2006 Grant - Koldamova
LXR Receptors and Alzheimer's Disease
Radosveta Koldamova, M.D., Ph.D.
University of Pittsburgh
2006 Investigator-Initiated Research Grant
Although numerous health studies have reported an association between Alzheimer's disease and cholesterol, the link between the two is not well understood. But one facet that scientists have been keeping a close eye on is the transport of cholesterol into and out of cells. This is because two proteins that help shuttle cholesterol across cell membranes-apolipoprotein E and ATP-binding cassette transporter A1 (ABCA1)-have been linked to production of beta-amyloid, a small protein fragment that is believed to be a major trigger of Alzheimer pathology. Variations in the genes for apolipo-protein E and ABCA1 have also been linked to increased risk for developing the disease.
Because production of ABCA1 is controlled by a set of proteins called liver X receptors (LXRs), these proteins are also being scrutinized. Radosveta Koldamova, Ph.D., and colleagues found that specific ligands, or molecules that activate LXRs, increase production of ABCA1 and decrease production of beta-amyloid in cultured neurons. In genetically altered mice with Alzheimer-like pathology, these molecules have similar effects, reducing the amount of beta-amyloid produced in the brain. Dr. Koldamova and colleagues plan to investigate the relationship between LXRs and Alzheimer's disease in more detail.
The researchers will examine how LXRs are involved in the production of beta-amyloid. They will focus on the major role of LXRs, which is to regulate the turning on and off of genes. They will examine which LXR gene targets may be involved in the production of beta-amyloid and whether or not LXR ligands can alter the Alzheimer-like pathology that is found in mouse models of the disease. Their findings may improve our understanding of how beta-amyloid is produced and could open up new avenues for therapeutic exploration.