Understanding the Molecular Details of Amyloid Formation

               Protein aggregates known as amyloid plaque are deposited in the brains of Alzheimer’s disease (AD) victims. Althou gh a causal link between amyloid deposition and AD has not been proven, there is increasing evidence that plaque formation may lead to nerve cell degeneration. We are interested in the factors which influence amyloid formation. These may relate to the chemical structure of the plaque-forming protein  ß-protein) or to the unusual conditions in a diseased brain.                Because only minute quantities of the amyloid protein are available from natural sources (autopsy), we have undertaken a chemical synthesis of the protein. The synthesis, which at this time is nearly complete, has been complicated by the peculiar properties of the P-protein. New chemical techniques have been developed to solve these problems. Aside from allowing us to obtain large quantities of pure ß-protein for structural studies, the chemical synthesis facilitates the preparation of chemically labelled analogs of the P-protein. Judicious placement of these labels will greatly increase the power of traditional methods of structure determination.               The first section of this proposal concerns using the synthetic P-protein and labelled analogs to create a detailed, testable model for the molecular architecture of the amyloid plaque. Once we unders tand the structure of the plaque, we intend to design molecules which may inhibit its formation. The design of these molecules, which are potential antiAlzheirner’ s disease drugs, is the subject of the second part of this proposal.               Our investigative approach can be unde rstood in terms of an analogy between the amyloid plaque and a complicated brick wall. In order to unders tand how the bricks fit together, we must first know the structure of each brick. In this case, the ß-prote in is equivalent to a brick. The question of how the bricks fit together is critical to our research. Since our ultimate goal is to interfere with this interaction , our strategy is to construct “decoy” bricks which initially fit into the wall but prevent the completion of the wall or that, once incorporated, cause a structural defect which reduces the wall to a pile of bricks. We hope that this approach will lead to a pharmaceutical strategy against amyloid d eposition and Alzheimer’s disease.