To view an abstract, select an author from the vertical list on the left.
2006 Grant - Landreth
Mechanisms of Statin-Mediated Regulation of APP Metabolism
Gary Landreth, Ph.D.
Case Western Reserve University
2006 Investigator-Initiated Research Grant
Because high levels of cholesterol have been shown to increase one's risk for Alzheimer's disease, many researchers have wondered if statins, the most widely prescribed cholesterol-lowering medications worldwide, may protect against the disease. Results from some small studies suggest that statins may indeed decrease risk for Alzheimer's, but scientists are still debating why this may be. Because statins also lower levels of a different class of lipids called isoprenoids, there have been suggestions that isoprenoid reduction, rather than reductions in cholesterol, may explain the effect of statins on Alzheimer's disease processes.
Gary Landreth, Ph.D., and colleagues will test this hypothesis. Specifically, they plan to examine the links between isoprenoids, Alzheimer's disease and a group of molecules called G-proteins. Not only do isoprenoids inhibit G-proteins, but the G-proteins have also been implicated in the biology of amyloid precursor protein (APP). APP is a large membrane-bound protein that gives rise to beta-amyloid, a small protein fragment that is toxic to neurons and is believed to be a key trigger of Alzheimer pathology.
Landreth and colleagues will focus on the role of the G-protein Rab because it has been linked to the transport of APP to the cell membrane. The researchers will first determine if Rab is inhibited by isoprenoids. Next they will test if that inhibition affects APP transport to the cell membrane. They will also examine if the effect of isoprenoids on Rab may alter the delivery of APP to synapses, specialized junctions between neurons that are involved in cell-to-cell communication. That communication is critical for the learning and memory processes that are lost as Alzheimer's disease progresses.
This work may lead to a new understanding of the role of isoprenoids and G-proteins in Alzheimer's and could lead to new therapeutic agents that specifically target isoprenoids.