Project DetailsChanges in the activity of specific brain proteins lead to an increase in beta-amyloid protein, cell death, and loss of memory in Alzheimer's disease. Dr. Masuo Ohno and colleagues are looking at three protein “players” that increase the levels of beta-amyloid expression, including GCN2, eIF2alpha, and BACE1. The GCN2 protein adds a special chemical group, called a “phosphate,” to the eIF2alpha protein. This changed eIF2alpha then elevates BACE1, a key enzyme responsible for beta-amyloid production. The changed eIF2alpha also suppresses the activity of the CREB protein. CREB helps memories to form, so reducing its activity is bad news for the brain. To break this dual harmful cycle, they will remove the GCN2 gene from mice with Alzheimer's disease so that a phosphate won't be added to eIF2alpha and, therefore, won't elevate BACE1 or suppress CREB. Stopping the BACE1 elevation and the loss of CREB activity could improve the memories of these mice. Their discoveries will help to understand the key chemical changes that happen as Alzheimer's disease progresses, and could lead to new possibilities for disease-modifying drugs.