Alzheimer's disease (AD) is a major catastrophic illness within our aging population. At present there is no treatment for this disease. The cumulative evidence suggests that amyloid beta peptide is directly involved, probably via its direct toxicity to cells. If A-beta toxicity could be prevented, then the progress of the disease may be slowed or halted. It is the goal of this proposal to understand at the biochemical level the initial phases of A-beta toxicity. We will attempt to identify and clone the enzyme responsible for superoxide or hydrogen peroxide production which is observed immediately following the addition of A-beta to cells. In addition, we will identify the enzyme which is responsible for the reduction of the tetrazolium dye, MTT. Several laboratories have shown that the inactivation of this unknown enzyme is one of the earliest markers for A-beta toxicity, and that it could be linked to free radical production in A-beta treated cells. Since both enzymes appear to be critical early steps in A-beta toxicity, understanding their structure and chemistry could lead to a unique clinical approach to AD.
