Mechanisms of Amyloidogenesis of Beta-Amyloid Peptide

       Alzheimer’s disease is a disorder that afflicts more than two million Americans and kills at least 100,000 every year. It is estimated that 20-30% of people over the age of 80 have the disease. Alzheimer’s patients suffer from symptoms such as memory decline, disorientation, 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 sub stantial scientific investigation.           Considerable interest has recently focused on the role that a protein, called beta-amyloid peptide, 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. Evidence is mounting that beta-amyloid peptide can cause nerve cell degeneration in laboratory experiments. However, the method by which the peptide exerts its destructive effects is unknown. A number of other components of senile plaques which may associate with beta-amyloid peptide have been identified; but their roles in the disease process are not understood.          Under an electron microscope, beta-amyloid peptide deposits in senile plaques look like bundles of thin, long fibers. The deposits result because the protein aggregates into these structures. Understanding the physical structure of the amyloid deposits and the mechanisms of assembly of the components into fibers and bundles may be crucial in determining what role beta-amyloid peptide plays in the development of Alzheimer’s disease. For example, some research suggests that dep osition of beta-amyloid protein in amorphous form precedes formation of fibrils, and that the fibril structures is necessary to cause brain damage. As another example, beta-amyloid peptide may cause abnormal growth of nerve cells only when it is in its unaggregated form.          We are investigating how and why beta-amyloid peptide aggregates into fibrillar or amorphous deposits, and the role that a number of other components may play in this process. To do this, synthetic peptides that mimic the naturally-occuring beta-amyloid peptide are chemically produced. A variety of experimental techniques are used to determine the conditions that lead to aggregatio n and the size and structure of the aggregated peptide. The effect that other components may have on enhancing or inhibiting aggregation is probed using the same methods. A mathematical model describing the pathway that beta-amyloid peptide and other components take in forming amyloid fibrils is under development. This work should aid in clarifying the physiological role of beta-amyloid peptide and other components of amyloid deposits in Alzheimer’s disease. In turn, this should help in devising new, effective methods to diagnose and treat this debilitating disease.