We hypothesize that amyloid B-protein (AB) assembly into oligomers and polymers is a seminal neuropathogenetic process in Alzheimer's disease (AD). A direct prediction of this hypothesis is that inhibiting formation of, or disrupting, AB assemblies would be of benefit in the treatment of AD. Detailed knowledge of the tertiary and quaternary structure of AB at each stage of fibril formation would facilitate the design of fibrillogenesis inhibitors. Unfortunately, the three-dimensional structure of AB, both in its monomeric and assembled states, has not been fully elucidated at the molecular level. This proposal seeks to determine the spatial interactions occurring among amino acid side-chains within prefibrillar and fibrillar AB assemblies and then to use these data as distance constraints to construct a dynamic, three-dimensional model of AB fibril assembly. The experimental approach proposed takes advantage of a novel method for """"""""Photo-Induced Cross-linking of Unmodified Proteins"""""""" (PICUP). This method provides the means to construct a topological map of the interfaces among AB molecules, without pre factostructural modification of AB and under physiological conditions. In addition to providing valuable information relevant to AD, the results of the work could have broad import because fibrils from a variety of evolutionarily unrelated proteins and peptides appear to share a common core amyloid structure. Two primary aims and four subaims constitute this proposal:
Aim 1. To identify interacting amino acids within monomeric AB, and within and between AB, molecules composing higher order AB assemblies.
Aim 1 A. To identify interacting amino acids within monomeric AB.
Aim lB. To identify interacting amino acids within low order AB oligomers.
Aim 1 C. To identify interacting amino acids in AB protofibrils and AB-derived diffusible ligands (ADDLs).
Aim I D. To identify interacting amino acids in AB fibrils.
Aim 2. To construct an experimentally-based, dynamic, three-dimensional model of AB fibril assembly.
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