2008 Grants - Ferreira

Cholesterol and the Susceptibility of Aging Neurons to Abeta Toxicity

Adriana Ferreira, M.D., Ph.D.
Northwestern University - Chicago Campus
Chicago, Illinois

2008 Investigator-Initiated Research Grant

Alzheimer's disease is characterized by toxic clumps of the protein fragment beta-amyloid and the protein tau. Beta-amyloid tends to accumulate into plaques in the Alzheimer brain. Tau, which ordinarily helps maintain the internal structure of neurons, becomes abnormally modified in Alzheimer's disease and forms harmful tangles.

A growing body of evidence suggests that toxic beta-amyloid may help trigger the abnormal modification of tau. However, the biological mechanisms linking beta-amyloid and tau pathology are not completely known. Recent studies have found that beta-amyloid clumping may induce the activation of certain enzymes. These enzymes, in turn, may help produce abnormal tau.

In earlier experiments with cultured neurons, Adriana Ferreira, M.D., Ph.D., and colleagues were able to generate abnormal tau by using beta-amyloid to activate an enzyme called calpain. Moreover, the researchers found that certain neurons were more susceptible than others to this toxic process. Dr. Ferreira's team hypothesizes that cholesterol content in the membranes of neurons helps determine whether they will become vulnerable to amyloid-induced tau alteration.

For this proposed grant, Dr. Ferreira's team will test their hypothesis using 1) cultured neurons, 2) neurons obtained from animals engineered to develop Alzheimer-like symptoms, and 3) neurons from autopsied brain tissue of people with Alzheimer's disease. The researchers will measure the membrane cholesterol content of these cells. They then will analyze whether differences in cholesterol content affect how the neurons respond to toxic beta-amyloid.

Results from this study could shed new light on how beta-amyloid, tau and cholesterol are linked in Alzheimer's disease. Such knowledge could lead to novel therapies for the disease.