Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells

Human pancreatic islet amyloid polypeptide (hIAPP) and beta amyloid (A beta) can accumulate in Type 2 diabetes (T2D) and Alzheimer's disease (AD) brains and evidence suggests that interaction between the two amyloidogenic proteins can lead to the formation of heterocomplex aggregates. However, the structure and consequences of the formation of these complexes remains to be determined. The main objective of this study was to characterise the different types and morphology of A beta -hIAPP heterocomplexes and determine if formation of such complexes exacerbate neurotoxicity. We demonstrate that hIAPP promotes A beta oligomerization and formation of small oligomer and large aggregate heterocomplexes. Co-oligomerized A beta 42-hIAPP mixtures displayed distinct amorphous structures and a 3-fold increase in neuronal cell death as compared to A beta and hIAPP alone. However, in contrast to hIAPP, non-amyloidogenic rat amylin (rIAPP) reduced oligomer A beta -mediated neuronal cell death. rIAPP exhibited reductions in A beta induced neuronal cell death that was independent of its ability to interact with A beta and form heterocomplexes; suggesting mediation by other pathways. Our findings reveal distinct effects of IAPP peptides in modulating A beta aggregation and toxicity and provide new insight into the potential pathogenic effects of A beta -IAPP hetero-oligomerization and development of IAPP based therapies for AD and T2D.