The amyloid beta-amylin interaction: a molecular link between diabetes and Alzheimer’s disease
Clinical studies have shown that type-2 diabetes (T2D) is associated with an increased risk of dementia, including Alzheimer’s disease (AD). The molecular mechanisms behind this association are, however, not well understood. Both of these age-related, chronic diseases feature the accumulation of amyloid protein aggregates (beta amyloid or Aβ in the brain in AD and amylin in the pancreas in T2D). Recent studies at Curtin University suggest that Aβ and amylin can co-exist in AD brain and synergistically interact to potentiate cell death and amyloid deposition. These findings suggest that amylin may modulate the aggregation of Aβ, forming stable hetero-complexes with increased toxicity. The direct interaction of these amyloid proteins is poorly understood, but could play a major role in the genesis and progression of pathological conditions in the brain and pancreas. A number of recent molecular modelling studies have attempted to characterise the structure of amylin and Aβ-amylin oligomers.
This project will use molecular modelling approaches to study the interactions of Aβ and amylin and the structure of Aβ-amylin complexes. Molecular dynamics (MD) simulations will be used to investigate the nature and affinity of the interactions between Aβ and amylin, the structure of the complexes formed and the factors that control them. The findings will be compared and validated with data obtained from surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), circular dichroism (CD) and thioflavin-T aggregation assays, such that a full characterization of the kinetics and affinity of binding between Aβ and amylin can be obtained, including changes to their structure upon the formation of their complexes. The outcomes of this project will shed much needed light into the cross-seeding mechanisms that underlie the pathological roles of these proteins in AD and T2D.