Kinetics of Peptide Aggregation in Neurodegenerative Disease

Abstract

Peptide aggregation is linked to Alzheimer's (Aβ), Huntington's (polyglutamine expansion in huntingtin), and other neurodegenerative diseases, motivating our studies into the kinetics of aggregation. Polyglutamine peptides have been used as models of aggregation. The accepted hypothesis is that these peptides aggregate via nucleated polymerization whereby the nucleus is a β‐sheet monomer. We examined polyglutamine peptide aggregation experimentally, and conclude that it is more likely that polyglutamine peptides first associate into large oligomers that lack defined secondary structure, which then slowly rearrange to β‐sheet aggregates. Additionally, we examined the role of polyglutamine length on the structure, stability, and aggregation properties of a host protein. We have carried out extensive investigations into Aβ; aggregation kinetics. Here too, our data are consistent with a model in which Aβ; first assembles into oligomers that lack secondary structure, and then mature into insoluble β‐sheet fibrils. Currently we are pursuing the hypothesis that transthyretin (TTR) may be protective against Aβ toxicity. We examined the effect of several TTR variants on Aβ and saw a strong correlation between acceleration of aggregation and inhibition of toxicity. Preliminary data suggests that the stability of TTR tetramers plays a strong role in regulating TTR‐Aβ interactions.