Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells
Prashant Bharadwaj, Edith Cowan UniversityFollow
Guiseppe Verdile, Edith Cowan UniversityFollow
Charles S. Bond
Ralph Martins, Edith Cowan UniversityFollow
Nature Scientific Reports
Centre of Excellence for Alzheimer’s Disease Research and Care / School of Medical and Health Sciences
Edith Cowan University - Open Access Support Scheme 2020
NHMRC Dementia research development fellowship
NHMRC Number : 1107109
Human pancreatic islet amyloid polypeptide (hIAPP) and beta amyloid (Aβ) 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 Aβ-hIAPP heterocomplexes and determine if formation of such complexes exacerbate neurotoxicity. We demonstrate that hIAPP promotes Aβ oligomerization and formation of small oligomer and large aggregate heterocomplexes. Co-oligomerized Aβ42-hIAPP mixtures displayed distinct amorphous structures and a 3-fold increase in neuronal cell death as compared to Aβ and hIAPP alone. However, in contrast to hIAPP, non-amyloidogenic rat amylin (rIAPP) reduced oligomer Aβ-mediated neuronal cell death. rIAPP exhibited reductions in Aβ induced neuronal cell death that was independent of its ability to interact with Aβ and form heterocomplexes; suggesting mediation by other pathways. Our findings reveal distinct effects of IAPP peptides in modulating Aβ aggregation and toxicity and provide new insight into the potential pathogenic effects of Aβ-IAPP hetero-oligomerization and development of IAPP based therapies for AD and T2D.
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Bharadwaj, P., Solomon, T., Sahoo, B.R., Ignasiak, K., Gaskin, S., Rowles, J., ... & Martins, R. N. (2020). Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells. Scientific Reports, 10 Article 10356. https://doi.org/10.1038/s41598-020-66602-9