Balance between Association and Dissociation Rate Constants Determines Morphology and Property of Amyloid Fibrils.

A parallel dimeric Aβ(1-40) peptide was prepared, and its structural and fibrillogenic characteristics were examined. The covalent linking of the peptide strongly facilitated the spontaneous formation of thioflavin-T-active, fibrillar aggregates rich in β strands without a lag phase. However, the aggregates formed by the dimeric peptide did not exhibit "seeding activity" to catalyze the formation of amyloid fibrils by wild-type Aβ(1-40) molecules. Heteronuclear NMR analysis revealed that an isolated dimeric molecule in reverse micelles lacked ordered secondary structures. It was therefore considered that excessively high hydrophobicity caused by dimerization was the major reason for the rapid formation of amorphous aggregates without seeding activity. A hundred-fold dilution of the concentration of dimeric peptides reproduced the aggregation kinetics with a preceding lag phase of several hours, similar to that of wild-type molecules. The resulting aggregates exhibited a typical amyloid fibril-like morphology and, importantly, possessed seeding activity for wild-type peptides. The present results emphasize the importance of an appropriate balance between association and dissociation rate constants for the formation of "one-dimensional crystalline" amyloid fibrils.