Dissecting the Role of Single Regions of an IAPP Mimic and IAPP in Inhibition of Aβ40 Amyloid Formation and Cytotoxicity

Alzheimer's disease (AD) and type 2 diabetes (T2D) are linked to the self‐association of β‐amyloid peptide (Aβ) and islet amyloid polypeptide (IAPP), respectively. We have shown that IAPP‐GI, a soluble IAPP analogue and mimic of nonamyloidogenic and nontoxic IAPP, binds Aβ with high affinity and blocks its cytotoxic self‐assembly and fibrillogenesis. We have also shown that IAPP and Aβ interact with each other into nonfibrillar and nontoxic heterocomplexes that suppress cytotoxic self‐association by both polypeptides. The Aβ–IAPP interaction might thus be a molecular link between AD and T2D. We studied the role of individual IAPP‐GI and IAPP regions in their inhibitory function on Aβ40 self‐association and cytotoxicity. We found that the presence of the two hot‐spot regions of the Aβ–IAPP interaction interface in IAPP(8–28) is not sufficient for inhibitory function and that, in addition to IAPP(8–28), the presence of the N‐terminal region IAPP(1–7) is absolutely required. By contrast, the C‐terminal region, IAPP(30–37), is not required although its presence together with IAPP(1–7) in IAPP‐GI results in a marked enhancement of the inhibitory effect as compared to IAPP(1–28)‐GI. We suggest that the inhibitory effect of IAPP‐GI and IAPP on Aβ40 fibrillogenesis and cell toxicity is mediated primarily by interactions involving the hot regions of the Aβ–IAPP interaction interface and the N terminus of IAPP while a concerted and likely structure‐stabilizing action of the N‐ and C‐terminal IAPP regions potentiates this effect. These results identify important molecular determinants of the amyloid suppressing function of the Aβ40–IAPP interaction and could contribute to the design of novel inhibitors of Aβ40 aggregation and cell degeneration. Block buster: We have previously found that the interaction of the type 2 diabetes islet amyloid polypeptide (IAPP) and its nonamyloidogenic mimic IAPP‐GI with the Alzheimer's disease β‐amyloid peptide (Aβ) blocks Aβ aggregation and cytotoxicity. Here we uncover the role of individual IAPP‐GI and IAPP regions in the inhibitory function on Aβ40 amyloidogenesis and cytotoxicity and suggest a molecular basis for this effect.