Lecanemab blocks the effects of the Aβ/fibrinogen complex on blood clots and synapse toxicity in organotypic culture

• 成果类型: Article
• 署名作者: Singh, Pradeep Kumar; Pires, Elisa Nicoloso Simoes-; Chen, Zu- Lin; Torrente, Daniel; Calvano, Marissa; Sharma, Anurag; Strickland, Sidney; Norris, Erin H.
• 署名单位: Rockefeller University; Rockefeller University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13491
• DOI: 10.1073/pnas.2314450121
• 发表日期: 2024-04-23
• 关键词: alzheimers-disease; cognitive decline; beta; fibrinogen; hippocampus; thrombosis

摘要

Proteinaceous brain inclusions, neuroinflammation, and vascular dysfunction are common pathologies in Alzheimer's disease (AD). Vascular deficits include a compromised blood-brain barrier, which can lead to extravasation of blood proteins like fibrinogen into the brain. Fibrinogen's interaction with the amyloid-beta (A beta) peptide is known to worsen thrombotic and cerebrovascular pathways in AD. Lecanemab, an FDA-approved antibody therapy for AD, clears A beta plaque from the brain and slows cognitive decline. Here, we show that lecanemab blocks fibrinogen's binding to A beta protofibrils, preventing A beta/fibrinogen-mediated delayed fibrinolysis and clot abnormalities in vitro and in human plasma. Additionally, we show that lecanemab dissociates the A beta/fibrinogen complex and prevents fibrinogen from exacerbating A beta-induced synaptotoxicity in mouse organotypic hippocampal cultures. These findings reveal a possible protective mechanism by which lecanemab may slow disease progression in AD.