Structure and Dynamics of Beta-Amyloid Protein Aggregation

      Alzheimer’s disease is a disorder that afflicts more than two million Americans and kills about 100,000 every year. About 20% of people over the age of 80 are believed to have the disease. A l zheimer’s patients suffer from symptoms such as memory decline, disorie ntation, personality changes, and communication difficulties. The disease is characterized by the presence of senile plaques and tangles in the brain, with the number of plaques increasing with the severity of the disease. How the plaques and tangles are related to the disease process remains controversial despite substantial scientific investigation .             Considerable interest has recently focused on the role that a protein, called beta-amyloid protein, may play in causing senile plaques. This protein has been identified as a major component of the plaques and has also been detected in the skin and intestine of Alzheimer’s patients. Deposition of beta-arnyloid protein in the brain may be the initial step which triggers tissue damage by causing nerve cells to sprout abnormally. Associated with beta-amyloid protein in senile plaques are at least two other components: a protein called alpha-1-antichymotrypsin and aluminum. The role of these components in the formation of the plaques and in the development of the disease is uncertain.            Under an electron microscope, beta-arnyloid protein deposits in senile plaques look like loose bundles of thin, long fibers. The deposits res ult because the protein aggregates together into a gel-like material. Although beta-amyloid protein deposition occurs in many parts of the brain and in other parts of the body, tissue damage occurs only in the cerebral cortex, which is the part of the brain responsible for higher-level functions such as language and thought processes. Recently it has bee n suggested that the deposi ts that occur in sites where brain damage does not occur have an amorphous rather than fibrous structure.            Research into the role of arnyloid plaques in Alzheimer’s disease has focused primarily on characterizing the chemical components of the plaques. However, understanding the physical structure of the plaques and the mechanisms of assembly of the protein components into fibers and bundles may be equally important. For example, some research suggests th at deposition of betaamyloid protein in amorphous form precedes formation of fibers, and that the fibrous structure is necessary to cause brain damage. As another example, beta-arnyloid prote in may cause a bnormal growth of nerve cells only when it is in its unaggregated form.            Therefore, we are investigating how and why beta-arnyloid protein aggregates into fibrous or amorphous deposits. To do this, synthetic proteins that mimic the naturally-occurring betaarnyloid protein will be produced. The temperature and concentration at which aggregation occurs will be measured, as will th e protein concentration in the solution. These experiments will establish the cond itions which will lead to aggregation and will determine whether some unaggregated betaamyloid protein remains in solution at equilibrium, available to cause abnormal growth of nerve cells. The rate of aggregation of the protein will be de termined by using two techniques called quasi-elastic light scattering and classical light scattering. In these experiments, a laser beam is used to measure the size of the protein aggregates. The structure of the insoluble aggregate will be explored using a new technique called forced Rayleigh scattering. In this technique, the speed with