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RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity
Andisheh Abedini, … , Daniel P. Raleigh, Ann Marie Schmidt
Andisheh Abedini, … , Daniel P. Raleigh, Ann Marie Schmidt
Published January 16, 2018
Citation Information: J Clin Invest. 2018;128(2):682-698. https://doi.org/10.1172/JCI85210.
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Research Article Cell biology Article has an altmetric score of 4

RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity

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Abstract

Islet amyloidosis is characterized by the aberrant accumulation of islet amyloid polypeptide (IAPP) in pancreatic islets, resulting in β cell toxicity, which exacerbates type 2 diabetes and islet transplant failure. It is not fully clear how IAPP induces cellular stress or how IAPP-induced toxicity can be prevented or treated. We recently defined the properties of toxic IAPP species. Here, we have identified a receptor-mediated mechanism of islet amyloidosis–induced proteotoxicity. In human diabetic pancreas and in cellular and mouse models of islet amyloidosis, increased expression of the receptor for advanced glycation endproducts (RAGE) correlated with human IAPP–induced (h-IAPP–induced) β cell and islet inflammation, toxicity, and apoptosis. RAGE selectively bound toxic intermediates, but not nontoxic forms of h-IAPP, including amyloid fibrils. The isolated extracellular ligand–binding domains of soluble RAGE (sRAGE) blocked both h-IAPP toxicity and amyloid formation. Inhibition of the interaction between h-IAPP and RAGE by sRAGE, RAGE-blocking antibodies, or genetic RAGE deletion protected pancreatic islets, β cells, and smooth muscle cells from h-IAPP–induced inflammation and metabolic dysfunction. sRAGE-treated h-IAPP Tg mice were protected from amyloid deposition, loss of β cell area, β cell inflammation, stress, apoptosis, and glucose intolerance. These findings establish RAGE as a mediator of IAPP-induced toxicity and suggest that targeting the IAPP/RAGE axis is a potential strategy to mitigate this source of β cell dysfunction in metabolic disease.

Authors

Andisheh Abedini, Ping Cao, Annette Plesner, Jinghua Zhang, Meilun He, Julia Derk, Sachi A. Patil, Rosa Rosario, Jacqueline Lonier, Fei Song, Hyunwook Koh, Huilin Li, Daniel P. Raleigh, Ann Marie Schmidt

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Figure 3

sRAGE targets prefibrillar h-IAPP LP intermediates and inhibits amyloid formation.

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sRAGE targets prefibrillar h-IAPP LP intermediates and inhibits amyloid ...
(A) Thioflavin-T–monitored kinetics of h-IAPP amyloid formation after the addition of sRAGE at different time points (15°C). Arrows indicate the time points at which sRAGE was added to different kinetic species of h-IAPP: prefibrillar ELP species (orange), prefibrillar MLP species (green), fibrillar GP species (purple), and SP amyloid fibrils (blue). h-IAPP without sRAGE (red) was used as a positive control for amyloid formation. (B) Difference-CD studies showed the effect of sRAGE on h-IAPP secondary structure formation: t0 species (black), ELP species (orange), MLP species (green), LLP species (purple), and SP amyloid fibrils (blue). CD spectra of samples were recorded after a 48-hour incubation. h-IAPP readily formed amyloid by itself in the absence of sRAGE (red), but sRAGE inhibited β-sheet formation when added to h-IAPP at time points before the formation of toxic LP intermediates or when they were present, demonstrating that inhibition by sRAGE was sustained and not transient. The inhibitory effects of sRAGE on h-IAPP β-sheet formation decreased as it was added to h-IAPP at later time points in the LP. (C–H) Representative TEM images show the morphology of protein species at time points assessed by difference-CD. (C) Amorphous sRAGE alone, (D) h-IAPP SP amyloid fibrils, and the effect of the addition of sRAGE on different h-IAPP kinetic species: (E) ELP species, (F) MLP species, (G) LLP species, and (H) SP amyloid fibrils. Scale bars: 200 nm. The final peptide concentration in biophysical experiments was 20 μM. Thioflavin-T, CD, and TEM data are representative of 3 to 5 independent experiments. Data in A represent the mean ± SD of 3 to 6 technical replicates per time point. Error bars for some data points are smaller than the size of the symbols. incub, incubation.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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