2004 Investigator-Initiated Research Grant

Beta-amyloid is a protein fragment that may be a key factor in damaging cell-to-cell communication and causing the loss of brain cells in Alzheimer’s disease. Beta-amyloid is clipped from a larger molecule in a two-step process. The second cut is made by a team of proteins called gamma-secretase and occurs within the membrane surrounding a nerve cell.

Previous research has shown that this activity appears to be associated with lipid rafts, cholesterol-rich areas within the membrane structure. Understanding the molecular environment and interactions at the site of gamma-secretase activity may provide some clarification about factors that influence the normal and disease-related production of beta-amyloid.

Gopal Thinakaran, Ph.D., and colleagues are studying these particular site-specific events in cell cultures. They will conduct experiments to identify and characterize the molecular mechanisms that lead to gamma-secretase proteins “hooking up” with lipid rafts. They will also test the hypothesis that this gamma-secretase / lipid raft partnership has a function in regulating levels of beta-amyloid. They will evaluate the differences in beta-amyloid production when gamma-secretases are associated with lipid rafts and when they are associated with other membrane structures.

The outcome of this work may shed light on key steps in disease processes, explain complex interactions involved in gamma-secretase activity, and identify targets for new therapies that might safely and effectively disrupt beta-amyloid production.