Single-Molecular Heteroamyloidosis of Human Islet Amyloid Polypeptide

• Published in: Nano letters 2019-09, Vol.19 (9), p.6535-6546
• Main Authors: Kakinen, Aleksandr, Xing, Yanting, Hegoda Arachchi, Nuwan, Javed, Ibrahim, Feng, Lei, Faridi, Ava, Douek, Alon M, Sun, Yunxiang, Kaslin, Jan, Davis, Thomas P, Higgins, Michael J, Ding, Feng, Ke, Pu Chun
• Format: Article
• Language: English
• Subjects: Amyloidosis - drug therapy; Amyloidosis - metabolism; Animals; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Disease Models, Animal; Humans; Islet Amyloid Polypeptide - chemistry; Islet Amyloid Polypeptide - pharmacology; Microscopy, Atomic Force; Microscopy, Electron, Transmission; Protein Aggregation, Pathological - drug therapy; Protein Aggregation, Pathological - metabolism; Zebrafish - metabolism
• ISSN: 1530-6984; 1530-6992
• DOI: 10.1021/acs.nanolett.9b02771

Human amyloids and plaques uncovered post mortem are highly heterogeneous in structure and composition, yet literature concerning the heteroaggregation of amyloid proteins is extremely scarce. This knowledge deficiency is further exacerbated by the fact that peptide delivery is a major therapeutic strategy for targeting their full-length counterparts associated with the pathologies of a range of human diseases, including dementia and type 2 diabetes (T2D). Accordingly, here we examined the coaggregation of full-length human islet amyloid polypeptide (IAPP), a peptide associated with type 2 diabetes, with its primary and secondary amyloidogenic fragments 19–29 S20G and 8–20. Single-molecular aggregation dynamics was obtained by high-speed atomic force microscopy, augmented by transmission electron microscopy, X-ray diffraction, and super-resolution stimulated emission depletion microscopy. The coaggregation significantly prolonged the pause phase of fibril elongation, increasing its dwell time by 3-fold. Surprisingly, unidirectional elongation of mature fibrils, instead of protofilaments, was observed for the coaggregation, indicating a new form of tertiary protein aggregation unknown to existing theoretical models. Further in vivo zebrafish embryonic assay indicated improved survival and hatching, as well as decreased frequency and severity of developmental abnormalities for embryos treated with the heteroaggregates of IAPP with 19–29 S20G, but not with 8–20, compared to the control, indicating the therapeutic potential of 19–29 S20G against T2D.