Guojun Bu, Ph.D.
Washington University
St. Louis, Missouri

2004 Investigator-Initiated Research Grant

Beta-amyloid is a tiny protein fragment suspected of disrupting cell-to-cell communication and damaging cells in Alzheimer’s disease. Beta-amyloid is clipped from a molecule called amyloid precursor protein (APP). A number of researchers are looking at how APP normally works in brain cells, what molecules function as APP partners, and how their interactions may relate to Alzheimer’s disease processes.

Guojun Bu, Ph.D., and colleagues are investigating a class of proteins called low-density lipoprotein receptors, which function as “portals” for certain kinds of lipid (fat) compounds that cells need for normal function. In studies with cell cultures, the researchers found that a particular member of this class of receptors, known by the abbreviation LRP1B, interacts with APP. They also noted that if a cell had “boosted” levels of LRP1B, APP molecules tended to gather in such a way that, when they were broken down, very little beta-amyloid was produced.

In the current study, the research team will (1) examine cell cultures to characterize the possible role of LRP1B in APP function, (2) develop a line of genetically altered mice that enable a “live” investigation of LRP1B-APP interactions and (3) examine the potential of manipulating LRP1B levels to control beta-amyloid production. The outcome of this work may clarify the complex interactions and functions of APP and suggest new strategies for disease-modifying therapies.