Oxidative Damage in Alzheimer's Disease

Glycation, the oxidative reaction of sugars with proteins, has been established as a major source of oxidative damage in Alzheimer disease. Our studies implicate glycation as a path for the aggregation of proteins and also as a generator of neuronal oxidative stress in Alzheimer disease. Therefore, glycation likely plays a key role in the progression of the disease. Nonetheless, in order to understand the role of glycation and to use that knowledge to develop drugs to stop the progression of Alzheimer disease, the full extent of oxidative damage from various sources, including glycation, as well as the relationship of damage to nerve cells, must be known. This proposal is directed to addressing both issues; first, by determining the type and extent of oxidative damage with methods we have developed ourselves and, second, by using a cellular model to establish the relationship between oxidative damage and nerve cell death. This knowledge is of more than an academic interest since all drugs that affect the incidence or progression of Alzheimer disease, such as anti-inflammatory agents, iron chelators, vitamin E and estrogen, inhibit oxidative damage. Therefore, it appears that antioxidants offer the first approach to effectively treat patients suffering from Alzheimer disease. Our study will uncover the molecular mechanism(s) responsible for the benefit of antioxidant use and also speed the development of antioxidants specifically designed to stop the type of oxidative damage important in the pathogenesis of Alzheimer disease.