title: Molecular characterization of the hetero-assembly of β-amyloid peptide with islet amyloid polypeptide.
abstract: 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.
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Yan
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Velkova
authors.affiliation: Division of Peptide Biochemistry, Technische Universitat Munchen, Emil-Erlenmeyer-Forum 5, D- 85354 Freising, Germany. akapurniotu@wzw.tum.de.
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Kapurniotu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000633:toxicity; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity; D000686:Amyloidosis; D000818:Animals; D052160:Benzothiazoles; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000633:toxicity; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity; D011485:Protein Binding; D017510:Protein Folding; D055503:Protein Multimerization; D051381:Rats; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000737:chemistry
chemical_list: C509234:(N-Me)G24, (N-Me)I26-IAPP; D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C009462:thioflavin T