Aβ17–22 Derived Hexapeptide Segment Inhibits Islet Amyloid Polypeptide (IAPP) Aggregation and Attenuates Cytotoxicity

Abstract

Misfolding and aggregation of islet amyloid polypeptide (IAPP) are associated with the decline of β-cells in type 2 diabetes (T2D). Design of short peptide-based inhibitors of β-sheet-rich amyloid plaque formation is challenging due to the dynamic nature of the amyloid species. The key sequences involved in cross-amyloid interactions shed light on the design of peptide-based inhibitors. Amyloid-β peptide (Aβ) has nearly 50% similarity and 25% identity with IAPP sequences, and their cross-interactions have been suggested to link T2D pathogenesis with Alzheimer’s disease (AD). Here, we show that a short anionic amphiphilic hexapeptide (DM-P02) containing the Aβ domain (Leu17–Glu22) effectively suppresses aggregation and oligomerization of IAPP by predominantly interacting with its cationic N-terminus. DM-P02 also binds strongly to IAPP in pancreatic β-cell lines, as confirmed by confocal imaging, and protects them from IAPP aggregation-associated cytotoxicity. Our study underlines the therapeutic potential of short peptides for developing anti-amyloid agents.