Application). Several age-associated degenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease are characterized by the formation of fibrillar structures called amyloid plaques. The long-range goal of this work is to develop inhibitors of amyloidogenesis and to test whether or not such """"""""blocker"""""""" molecules can be effective suppressors of toxicity and ultimately therapeutic agents for amyloid associated diseases.
The specific aims and the hypotheses to be tested are: (1) Design and synthesis of new B-strand mimics that block the fibril and protofibril formation of the Alzheimer-associated B-amyloid peptide (All). Oligomerization of B-sheet structures, like those in A-Beta fibrils, can be inhibited or reversed by extended peptide structures that have only one edge available for hydrogen bonding. (2) Determination of the inhibition mechanism of protofibrillogenesis with B-strand mimics. Potentially neurotoxic protofibril formation can also be inhibited by """"""""blocker"""""""" molecules, the formation and dissolution of A-Beta protofibrils in the presence and absence of molecules known to inhibit fibril formation will be studied using scanning force microscopy (SFM), static light scattering (SLS), dynamic light scattering (DLS), analytical ultracentrifugation (AU) and fluorescence photobleaching recovery (FPR). (3) Detection of early intermediates in protofibril assembly by fluorescence photobleaching recovery (FPR) and AU and determination of molecularity of these early intermediates. Early aggregates can be dissociated in the presence of p-strand mimics. (4) Initiation of fibrillogenesis on hydrophobic and hydrophilic surfaces. Formation of protofibrils and fibrils of A-Beta in vivo is the result of interactions between soluble A-Beta and various moieties on the surface of neuronal cells and """"""""surface-induced"""""""" or nucleated A-Beta polymerization can be stopped or reversed by the presence of B-strand mimics. The potential impact of this work is gaining a better understanding of the etiology of AD and development of pharmaceutical agents for treating AD and other amyloid diseases.
