Increasing amounts of evidence suggest that Alzheimer's disease (AD) and type 2 diabetes (T2D) are linked to each other. We
have recently identified in vitro a high affinity interaction between β-amyloid peptide (Aβ) of AD and islet amyloid polypeptide (IAPP)
of T2D which results in the formation of non-fibrillar and non-cytotoxic Aβ-IAPP hetero-oligomers. The Aβ-IAPP interaction delays cytotoxic
self-association of both polypeptides albeit it is unable to block it. In this context, IAPP-GI, a soluble conformationally constrained
mimic of a non-amyloidogenic and non-toxic IAPP conformer, completely blocks Aβ amyloidogenesis and cytotoxicity. Here
we studied the hetero-association pathways of Aβ with IAPP and with IAPP-GI. We found that preformed Aβ or IAPP fibrils and cytotoxic
assemblies are able to seed amyloidogenesis and cytotoxicity in Aβ-IAPP but not in Aβ-IAPP-GI solutions. Initially non-fibrillar
and non-toxic Aβ-IAPP but not Aβ-IAPP-GI hetero-oligomers were found to further aggregate into hetero-fibrils and cytotoxic assemblies
in a process strongly enhanced under Aβ or IAPP self-assembly promoting conditions. Importantly, our studies provided evidence
that initially non-fibrillar and non-toxic Aβ-IAPP hetero-oligomers are able to misfold into hetero-fibrils and indicated a crucial role of
the strong amyloidogenic character of IAPP in this process. These results uncover a novel molecular property of the Aβ and IAPP sequences,
i.e. their ability to form hetero-fibrils, and offer mechanistic support to a model linking Aβ and IAPP hetero-association to their
cytotoxic self-association pathways and thus likely to the pathogenesis of AD and T2D.
Keywords: Amyloid fibrils, protein aggregation, β-amyloid peptide, islet amyloid polypeptide, Alzheimer's disease, type 2 diabetes.
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