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

Prashant Bharadwaj, Tanya Solomon, Bikash R. Sahoo, Katarzyna Ignasiak, Scott Gaskin, Joanne Rowles, Giuseppe Verdile, Mark J. Howard, Charles S. Bond, Ayyalusamy Ramamoorthy, Ralph N. Martins, Philip Newsholme

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number10356
JournalScientific Reports
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2020

Fingerprint Dive into the research topics of 'Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells'. Together they form a unique fingerprint.

  • Cite this

    Bharadwaj, P., Solomon, T., Sahoo, B. R., Ignasiak, K., Gaskin, S., Rowles, J., Verdile, G., Howard, M. J., Bond, C. S., Ramamoorthy, A., Martins, R. N., & Newsholme, P. (2020). Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells. Scientific Reports, 10(1), [10356]. https://doi.org/10.1038/s41598-020-66602-9