(93k) Identification of Therapeutic Targets for Alzheimer's Disease by Inhibitors of Amyloid-Beta Fibril Formation

Alzheimer's disease (AD) is the most common cause of dementia among people of age 65 and older. AD is characterized by the deposition of ?senile' plaques in the brain. The primary component of these plaques is the fibrillar form of the amyloid-beta protein (A-beta). These fibrils are formed via a nucleation dependent pathway. A soluble intermediate, the protofibril, has been identified along the fibrillogenesis pathway between the nucleus and the mature fibrils. Protofibrils can progress into larger fibrils via two distinct growth mechanisms: elongation by monomer deposition and protofibril-protofibril association. It is still unclear whether amyloid plaques themselves are central to AD pathogenesis, but increasing evidence suggests that amyloid deposition may be a central and defining process of the disease. By utilizing assays capable of isolating elongation and association mechanisms of protofibril growth, we tested three potential inhibitors, Trehalose, Betaine and Ectoine, for the effects of each on monomer nucleation, protofibril elongation and protofibril association. While Trehalose increased lag time to monomer nucleation, Betaine and Ectoine had no effect. In addition, none of the inhibitors affected protofibril growth by elongation, but protofibril association was found to be promoted or inhibited by Trehalose and Ectoine, respectively, while Betaine had no effect.