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Keywords:

  • Alzheimer's disease;
  • amyloid;
  • fibril;
  • peptide;
  • fluorescence

Senile plaques, the invariable hallmark and likely proximal cause of Alzheimer's disease (AD), are structured depositions of the 40- and 42-residue forms of the Aβ peptide. Conversely, diffuse plaques, which are not associated with neurodegeneration, consist mainly of unstructured Aβ42. We have investigated the interaction between Aβ40 and Aβ42 through an assay, which involves labeling both variants with an environment-sensitive fluorophore. We have monitored association of Aβ without fibrillar seeds, which allows investigation of molecular species preceding fibrils. Immediately upon mixture, Aβ40 and Aβ42 associate into mixed aggregates, in which the peptides are unstructured and relatively accessible to water. When left to incubate for an extended period, larger, more tightly packed aggregates, which show secondary structure, replace the small, unstructured aggregates formed earlier. Our results show that in vitro the two Aβ variants coassemble early in the fibrillogenesis pathway. The ease of formation for mixed and homogeneous aggregates is similar. A change in the local Aβ variant ratio can therefore have a significant impact on Aβ aggregation; indeed such a change has been reported in some types of familial AD.