Identifying Therapeutic Targets for Alzheimer's Disease by Inhibiting Amyloid-Beta Fibril Formation

Alzheimer's disease (AD) is the most common form of dementia in the elderly. 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. Soluble intermediates, or protofibrils, have been identified along this pathway between the nucleus and the mature fibrils. Protofibrils can progress into fibrils via two distinct growth mechanisms: elongation by monomer deposition and protofibril-protofibril association. The objective of this project was to explore a panel of peptides designed to bind A-beta protofibrils and inhibit protofibril growth at sub-stoichiometric concentrations. Peptides homologous to the hydrophobic core of A-beta, A-beta (16-20), were selected. This is the region that most efficiently binds A-beta, and this sequence is necessary for fibril formation. Laboratory experimentation revealed that KLVFF and KLVFY increased lag time to monomer nucleation, while KLVYY and KLVYF had no effect. None of the inhibitors affected protofibril growth by elongation, but for association an effect was observed by KLVFF. These results suggest that KLVFY is capable of binding nuclei to inhibit their growth, while KLVFF binds to the lateral surface of protofibrils to selectively target association.