Aggregation kinetics define the temporal window of IAPP proteotoxicity
- 1Department of Clinical Immunology, Copenhagen University Hospital – Rigshospitalet, Ole Maaloees Vej 26, 2200 Copenhagen N
- 2Department of Chemistry, Stony Brook University, Nichols Road, Stony Brook, NY, 11794-3400, USA
- 3Laufer Center for Physical and Quantitative Biology, Stony Brook University, Nichols Road, Stony Brook, NY, 11794, USA
Abstract
Aggregation of islet amyloid polypeptide (IAPP) to form amyloid contributes to β-cell dysfunction in type 2 diabetes, yet the identity and temporal persistence of the toxic species is unresolved. Competing models attribute toxicity to mature fibrils, fibril growth, or transient prefibrillar intermediates formed during the lag phase or via secondary nucleation. Here, we directly test these models by combining time-resolved β-cell functional assays with concurrent biophysical measurements of IAPP aggregation across multiple perturbations and sequence variants. Across 22 independent experiments spanning more than a 450-fold range in lag times, we find that maximal toxicity occurs during the lag phase and declines as fibrils accumulate. The duration of β-cell dysfunction scales linearly with lag phase length, establishing aggregation kinetics as a quantitative predictor of the onset, peak, and termination of toxicity. Perturbations that alter aggregation kinetics, including concentration, temperature, and sequence, predictably shift the temporal window of toxicity. The diabetes-associated S20G variant produces higher peak toxicity over a compressed time window, whereas the slower-aggregating variants examined prolong toxicity without increasing its magnitude. These results resolve competing models by demonstrating that transient lag-phase intermediates, rather than growth phase processes or mature fibrils, dominate β-cell dysfunction, and establish aggregation kinetics as a predictor of the timing and duration of cellular exposure to toxic intermediates.
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BibTeX
@article{plesner2026aggregation,
title = {{Aggregation kinetics define the temporal window of IAPP proteotoxicity}},
author = {Annette Plesner and Ping Cao and Daniel P. Raleigh and Andisheh Abedini},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = aug,
doi = {10.1073/pnas.2615786123},
url = {https://doi.org/10.1073/pnas.2615786123},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Aggregation kinetics define the temporal window of IAPP proteotoxicity
AU - Annette Plesner
AU - Ping Cao
AU - Daniel P. Raleigh
AU - Andisheh Abedini
PY - 2026
DA - 2026/08/06
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2615786123
UR - https://doi.org/10.1073/pnas.2615786123
AB - Aggregation of islet amyloid polypeptide (IAPP) to form amyloid contributes to β-cell dysfunction in type 2 diabetes, yet the identity and temporal persistence of the toxic species is unresolved. Competing models attribute toxicity to mature fibrils, fibril growth, or transient prefibrillar intermediates formed during the lag phase or via secondary nucleation. Here, we directly test these models by combining time-resolved β-cell functional assays with concurrent biophysical measurements of IAPP aggregation across multiple perturbations and sequence variants. Across 22 independent experiments spanning more than a 450-fold range in lag times, we find that maximal toxicity occurs during the lag phase and declines as fibrils accumulate. The duration of β-cell dysfunction scales linearly with lag phase length, establishing aggregation kinetics as a quantitative predictor of the onset, peak, and termination of toxicity. Perturbations that alter aggregation kinetics, including concentration, temperature, and sequence, predictably shift the temporal window of toxicity. The diabetes-associated S20G variant produces higher peak toxicity over a compressed time window, whereas the slower-aggregating variants examined prolong toxicity without increasing its magnitude. These results resolve competing models by demonstrating that transient lag-phase intermediates, rather than growth phase processes or mature fibrils, dominate β-cell dysfunction, and establish aggregation kinetics as a predictor of the timing and duration of cellular exposure to toxic intermediates.
SN - 0027-8424
SN - 1091-6490
ER -