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2008 Grants - Kang
Targeting the LRP Pathway for Abeta Reduction from Inside and Outside
David E. Kang, Ph.D.
University of California, San Diego
La Jolla, California
2008 Investigator-Initiated Research Grant
The protein fragment beta-amyloid tends to accumulate into clumps called plaques in the Alzheimer brain. Beta-amyloid is clipped from its parent molecule, amyloid precursor protein (APP). Evidence suggests that proteins called low-density lipoprotein receptor-related proteins (LRPs) help regulate beta-amyloid production by binding with APP.
Scientists classify LRPs and APP as transmembrane proteins. Parts of these proteins are intracellular, or reside inside the cell; and parts are extracellular, or reside outside the cell. Research has found that extracellular portions of LRPs tend to interact with extracellular APP in a way that promotes the breakdown of beta-amyloid. However, intracellular LRP interacts with intracellular APP in a way that promotes amyloid release.
In studies with cultured cells, David E. Kang, Ph.D., and colleagues found that the extent to which LRPs affect beta-amyloid production depends on the APP's structural makeup. The researchers focused specifically on a structural region called Kunitz protease inhibitor (KPI) domain, which exists in certain APP molecules. They found that when LRPs interact with APP proteins containing the KPI domain, this interaction produces unusually high levels of beta-amyloid. Dr. Kang's team believes that the KPI domain not only promotes amyloid production from intracellular APP, it also inhibits the ability of extracellular LRP and APP to break beta-amyloid down.
In other preliminary work, the researchers analyzed intracellular portions of LRPs to identify proteins that play crucial roles in the production of beta-amyloid. The team identified a particularly strong suspect protein called ran binding protein M (ranBPM).
For this proposal, Dr. Kang's team plans to study how APP molecules containing KPI domains may interact with LRPs to produce excess beta-amyloid. The researchers will also determine whether inhibiting the activities of ranBPM can reduce the production of beta-amyloid following APP-LRP binding. Both of these efforts will involve the use of cultured cells. The study's results could lead to novel therapeutic strategies for treating Alzheimer's disease.