Beta-amyloid peptide (A-beta) is the primary protein component of senile plaques in Alzheimer's disease (AD) patients. A-beta assembles into amyloid fibrils of 5-10 nm diameter, characterized by cross-beta conformation and birefringence upon Congo red staining. A-beta is toxic to neuronal cultures, and there is growing evidence that deposition of A-beta fibrils is central to the development of AD pathology. neurotoxicity of A-bet may require that the peptide adopt specific aggregational and/or conformational states. Despite this apparently obligatory requirement of fibrillogenesis to render A-beta toxic, the details of the A-beta assembly process and the fundamental role that A-beta assembly plays in A-beta-mediated neurotoxicity are still uncertain. There is some evidence that A-beta aggregation plays a significant role in binding of A-beta to cellular membranes, and that this binding is a key element in A-beta-mediated neurotoxicity. Substantial industrial and academic research effort is currently aimed towards identifying molecules which disrupt A-beta aggregation and, presumably, A-beta neurotoxicity. This process would be greatly aided by a more fundamental understanding of A-beta assembly and disassembly pathway and kinetics, and the role of aggregation in A-beta interactions with cells. The proposed project has two specific aims.
Specific aim 1 : A detailed mechanistic model of A-beta assembly and disassembly kinetics will be developed. To accomplish this, a series of experiments will be conducted to measure the rates of change in secondary structure, fibril length, and fibril number concentration, and the data will be used to construct and validate a quantitative mathematical model of A-beta assembly kinetics.
Specific aim 2 : Short peptides with partial homology to the central sequence of A-beta will be characterized for their ability to modulate A-beta aggregation kinetics and A-beta cytotoxicity. Several such peptides have already been synthesized; some of these peptides have been shown to alter A-beta aggregation kinetics or fibril changes in aggregation state to changes in cytotoxicity. Additionally, these short peptides may provide lead compounds for further development of therapeutics.
