An aminosterol breaks the autocatalytic cycle of Aβ42 aggregation and protects cell membranes from its soluble aggregates

• 成果类型: Article
• 署名作者: Fallot, Lucas B.; Pinc, Johnathan R.; Buselmeier, Joseph E.; Palchak, Julia C.; Shroff, Supria S.; Zang, Kaitlyn; Rinauro, Dillon J.; Bacon, Kate M.; Nguyen, Michael; Schleck, Mary Claire; Cornell, Alyssa R.; Oshidar, Alexandra; Darrell, Donald J.; Gabriel, Justus M.; Wright, Aidan K.; Sasser, Liam R.; Kreiser, Ryan P.; Burpo, F. John; Santambrogio, Alessia; Xu, Peifeng; Kubiak II, Robert W.; Loverde, Joseph; A.Jaffett, Victor; Toole, Justin R.; Barbut, Denise; Zasloff, Michael; Chiti, Fabrizio; Dear, AlexanderJ.; Vendruscolo, Michele; Limbocker, Ryan
• 署名单位: United States Military Academy; United States Department of Defense; United States Army; United States Military Academy; United States Department of Defense; United States Army; University of Cambridge; Georgetown University; University of Florence; Swiss Federal Institutes of Technology Domain; ETH Zurich; Swiss Federal Institutes of Technology Domain; ETH Zurich
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11701
• DOI: 10.1073/pnas.2417944122
• 发表日期: 2025-07-15
• 关键词: tyrosine-phosphatase 1b; alzheimers-disease; alpha-synuclein; nervous-system; oligomers; toxicity; ptp1b; mechanisms; inhibitor; leptin

摘要

Aberrant aggregates of the 42-residue form of the amyloid-f3 peptide (Af342) are cytotoxic in Alzheimer's disease (AD). Cost-effective and chronically safe disease-modifying therapeutics are needed to address the AD medical emergency worldwide. To increase our understanding of the mechanisms of Af342-induced cytotoxicity and to investigate clinically relevant aminosterols, we study the impact of claramine on the aggregation kinetics and properties of Af342 aggregates, as well as the ability of these proteotoxic species to bind and disrupt cell membranes. Whereas previously studied aminosterols accelerated Af342 aggregation, we show that claramine potently inhibits Af342 amyloid fibril formation. We find that claramine stabilizes soluble Af342, speeding up primary and secondary nucleation into species with antiparallel f3-sheet structure that are elongation incompetent, thereby depleting Af342 monomers from the aggregation reaction. This steroid-polyamine also dissociates Af342 fibrillar aggregates, resulting in the abrogation of the autocatalytic capacity of Af342 fibrils, and it also inhibits the aggregation of a tau fragment relevant to AD. Upon exposure of human neuroblastoma cells to stabilized Af342 oligomers, claramine effectively neutralized Af342 oligomer-induced cytotoxicity by preventing their binding to cell membranes. Owing to the unique mechanism of action of aminosterols to reduce the toxicity of soluble Af342 aggregates by protecting cell membranes, and the newly characterized ability of claramine to inhibit Af342 fibril formation and dissociate fibrillar Af342 resulting in the interruption of the positive feedback loop in Af342 aggregation, our findings further emphasize the relevance of this family of natural products as potential treatments for AD and other protein misfolding diseases.