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Current Pharmaceutical Design
ISSN (Print): 1381-6128
ISSN (Online): 1873-4286
VOLUME: 20
ISSUE: 8
DOI: 10.2174/13816128113199990064      Price:  $58









Molecular Characterization of the Hetero-Assembly of β-Amyloid Peptide with Islet Amyloid Polypeptide

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Author(s): Li-Mei Yan, Aleksandra Velkova and Aphrodite Kapurniotu
Pages 1182-1191 (10)
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.
Keywords:
Amyloid fibrils, protein aggregation, β-amyloid peptide, islet amyloid polypeptide, Alzheimer's disease, type 2 diabetes.
Affiliation:
Division of Peptide Biochemistry, Technische Universitat Munchen, Emil-Erlenmeyer-Forum 5, D- 85354 Freising, Germany.