Affiliation:
1. Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065
2. Electron Microscopy Resource Center, The Rockefeller University, New York, NY 10065
Abstract
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 (Aβ) peptide is known to worsen thrombotic and cerebrovascular pathways in AD. Lecanemab, an FDA-approved antibody therapy for AD, clears Aβ plaque from the brain and slows cognitive decline. Here, we show that lecanemab blocks fibrinogen’s binding to Aβ protofibrils, preventing Aβ/fibrinogen-mediated delayed fibrinolysis and clot abnormalities in vitro and in human plasma. Additionally, we show that lecanemab dissociates the Aβ/fibrinogen complex and prevents fibrinogen from exacerbating Aβ-induced synaptotoxicity in mouse organotypic hippocampal cultures. These findings reveal a possible protective mechanism by which lecanemab may slow disease progression in AD.
Funder
HHS | National Institutes of Health
Samuel Newhouse Family Foundation
John A. Herrmann
Zina Stern Postdoctoral Fellowship
May and Samuel Rudin Family Foundation
William J and Pam Michaelcheck
Publisher
Proceedings of the National Academy of Sciences
Cited by
1 articles.
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