- 2:35 PM
214f

Peptide Aggregation and Neurodegenerative Disease

Regina M. Murphy, Chemical and Biological Engineering, University of Wisconsin, 1415 Engineering Drive, Madison, WI 53706

Misfolding and aggregation of peptides lie at the root cause of several diseases, the most notable of which is Alzheimer's disease. In patients with this disease, fibrillar deposits of the peptide beta-amyloid in the brain are associated with neuronal dysfunction and death. Controlling beta-amyloid aggregation is of keen interest as a strategy for preventing Alzheimer's disease or minimizing its damage. We have developed experimental tools for monitoring the kinetics of beta-amyloid peptide aggregation, and derived a detailed kinetic model that sheds light on the mechanisms of aggregation. Rationalizing that compounds with a recognition domain (to bind to beta-amyloid) coupled to a disruption domain (to interfere with its normal aggregation pathway) may provide a means to control beta-amyloid aggregation and toxicity, we synthesized and tested a small library of short peptides with these features. Surprisingly, these peptides accelerated beta-amyloid aggregation but inhibited beta-amyloid toxicity. These data strongly support the hypothesis whereby misfolded oligomeric intermediates, rather than insoluble fibrillar aggregates, are the major pathological species. Using simple group contribution calculations, we show that the effective compounds act by modifying solvent properties. Finally, based on experiments in transgenic mice that indicate that another amyloidogenic protein, transthyretin, may actually confer protection against beta-amyloid toxicity, we have begun detailed examination of the association between transthyretin and beta-amyloid to infer the mechanism of protection.