TITLE: Molecular Lycanthropy: Alzheimer's Disease and Protein Refolding

SPEAKER: Professor David J. E. Callaway

TIME: Wednesday Mar. 6, 2002 at 4 PM

PLACE: George P. Williams, Jr. Lecture Hall, (Olin 101)

As many as four million people in the United States are incurably afflicted with Alzheimer's Disease (AD), a number that is predicted to increase to 14 million by the middle of the century. AD presently costs our society over $100 billion annually, and is a leading cause of death in this country. It is widely believed that the aggregation of the amyloid beta-peptide (Ab) into fibrils initiates a cascade of events that lead to dementia and death. The implied strategy of curing or preventing AD by the inhibition of Ab aggregation is therefore being pursued aggressively. In spite of the widely-appreciated need for a systematic, structure-based program for designing amyloid inhibitors, little progress has been made towards this goal. No high-resolution, three-dimensional structure of an amyloid fibril is known, and the forces that drive Ab fibril formation are not understood.

The determination of the molecular structure of Ab fibrils is a significant goal, for it would lead to the structure-based design of effective therapeutics for AD. Formidable technical challenges have thus far rendered this goal impossible by experimental technology alone. We therefore merge experimental technique with theoretical methodology. We have initiated a program of research that involves the direct design of amyloid fibrils themselves. By finding the molecular motifs necessary for fibril formation, the structural weak points of fibrils can be located. This provides a sound basis for developing a detailed molecular model from numerical simulation, and then testing its precepts experimentally. This combination of theory and experiment has led to the successful prediction and testing of a promising new compound for AD. It is expected that, by continuing this interdisciplinary program of theoretical and experimental research, significant progress could be made towards a cure for AD, and eventually towards a cure of the roughly 20 other "prion-like" diseases that exhibit similar pathology.