Effect of CholesterylEsters on PS1 and on ABeta Ratios

Dora Kovacs, PhD Massachusetts General Hospital

Project Details

High cholesterol levels have long been associated with atherosclerosis. Recent studies show that high cholesterol levels are also linked to the increased appearance of the senile plaques and neurofibrillary tangles characteristic of Alzheimer's disease. One possible explanation is that cholesterol inside the cellular membranes may somehow regulate the enzymes (secretases) that generate the amyloid beta peptide found in senile plaques. The cholesterol content in cellular membranes is maintained by the action of an enzyme called ACAT, which moves excess cholesterol from the membrane into the cell's cytoplasm in the form of insoluble lipid droplets. In earlier work, Dr. Kovacs found that decreased lipid droplets led to a decrease in the production of amyloid beta, whereas abnormally high levels of lipid droplets (even with normal membrane cholesterol levels) led to an increase in amyloid beta production. Dr. Kovacs suggests that the mechanism for this may involve the stabilization of presenilins, Alzheimer-associated proteins responsible for the production of amyloid beta. Dr. Kovacs is now exploring the mechanism by which presenilin activity and the production of amyloid beta may be regulated by lipid droplets. Understanding this mechanism could provide the basis for developing ACAT inhibitors that would lower amyloid beta generation and slow or prevent AD-related neuropathology.