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bioRxiv · 10.1101/2024.01.20.576458

Lecanemab Blocks the Effects of the Aβ/Fibrinogen Complex on Blood Clots and Synapse Toxicity in Organotypic Culture

Singh, P. K.·Simoes-Pires, E. N.·Chen, Z.-L.·Torrente, D.·Calvano, M.·Sharma, A.·Strickland, S.·Norris, E. H.
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Abstract

Proteinaceous brain inclusions, neuroinflammation, and vascular dysfunction are common pathologies in Alzheimers disease (AD). Vascular deficits include a compromised blood-brain barrier, which can lead to extravasation of blood proteins like fibrinogen into the brain. Fibrinogens 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, shows promising results in facilitating reduction of A{beta} from the brain and slowing cognitive decline. Here we show that lecanemab blocks fibrinogens binding to A{beta} protofibrils, normalizing 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.

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Singh, P. K., Simoes-Pires, E. N., Chen, Z.-L., Torrente, D., Calvano, M., Sharma, A., Strickland, S., Norris, E. H.. 2024-01-21. Lecanemab Blocks the Effects of the Aβ/Fibrinogen Complex on Blood Clots and Synapse Toxicity in Organotypic Culture. https://doi.org/10.1101/2024.01.20.576458

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