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LL-37 and Its Truncated Fragments Modulate Amyloid-β Dynamics, Aggregation and Toxicity Through Hetero-Oligomer and Cluster Formation
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0003-0905-7911
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Number of Authors: 92025 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773Article in journal (Refereed) Epub ahead of print
Abstract [en]

LL-37 and its variants with amphiphilic structure can modulate amyloid-β (Aβ) fibril formation, but the detailed mechanism behind it is still unclear. By using four different peptides (LL-37, LL-379–32, LL-3718–29, LL-3719–28), we found these peptides affect Aβ40 aggregation differently. Nanoscale analysis showed that all LL-37 peptides form hetero-oligomers and nanoclusters with Aβ40, but LL-37 and LL-3719–28, which exhibit the strongest inhibition of Aβ fibrillation, form more hetero-oligomers and smaller nanoclusters. This suggests that hetero-oligomers and small nanoclusters may represent an off-pathway, preventing the formation of productive aggregates. At the microscale, all LL-37 peptides were found to promote Aβ cluster formation, but LL-37 and LL-3719–28 can form larger clusters with Aβ rapidly, emphasizing that smaller nanoclusters can assemble to macroscale clusters easier, inducing more toxic aggregates. Both nanoscopic and microscopic mechanisms revealed inhibition of Aβ fibrillation by all LL-37 peptides, impacting Aβ primary and secondary nucleation, while only LL-37 and LL-3719–28 affected Aβ elongation. Our findings highlight the role of LL-37 and its synthetic fragments in Aβ40 aggregation across different scales, particularly focusing on cluster formation at the nanoscale and microscale to fill the knowledge gap between oligomerization and fibrillation.

Place, publisher, year, edition, pages
2025.
Keywords [en]
Amyloid-β40, Antimicrobial peptides, Cluster formation, Hetero-oligomer formation
National Category
Biochemistry
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URN: urn:nbn:se:su:diva-247483DOI: 10.1002/anie.202516241ISI: 001565209200001Scopus ID: 2-s2.0-105015434899OAI: oai:DiVA.org:su-247483DiVA, id: diva2:2001060
Available from: 2025-09-25 Created: 2025-09-25 Last updated: 2025-09-25

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Österlund, NicklasIlag, Leopold L.Gräslund, Astrid

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