Authors
Prashant Bharadwaj, Edith Cowan UniversityFollow
Tanya Solomon
Bikash Sahoo
Katarzyna Ignasiak
Scott Gaskin
Joanne Rowles
Guiseppe Verdile, Edith Cowan UniversityFollow
Mark Howard
Charles S. Bond
Ayyalusamy Ramamoorthy
Ralph Martins, Edith Cowan UniversityFollow
Philip Newsholme
Author Identifier
Prashant Bharadwaj
https://orcid.org/0000-0003-4361-9906
Giuseppe Verdile
https://orcid.org/0000-0003-2475-0124
Ralph Martins
Document Type
Journal Article
Publication Title
Nature Scientific Reports
Publisher
Springer Nature
School
Centre of Excellence for Alzheimer’s Disease Research and Care / School of Medical and Health Sciences
RAS ID
31904
Funders
Edith Cowan University - Open Access Support Scheme 2020
NHMRC Dementia research development fellowship
Grant Number
NHMRC Number : 1107109
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.
DOI
10.1038/s41598-020-66602-9
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
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