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

• DOI: 10.1073/pnas.2314450121
• Publication Date: 2024-04-15T19:06:53Z
• Authors: Pradeep Kumar Singh; Elisa Nicoloso Si...; Zu-Lin Chen; Daniel Torrente; Marissa Calvano; Anurag Sharma; Sidney Strickland; Erin H. Norris
• Keywords: Extravasation

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 amyloid-beta (Aβ) peptide is known worsen thrombotic cerebrovascular pathways AD. Lecanemab, an FDA-approved antibody therapy for AD, clears Aβ plaque from slows cognitive decline. Here, we show that lecanemab blocks fibrinogen’s binding protofibrils, preventing Aβ/fibrinogen-mediated delayed fibrinolysis clot abnormalities vitro human plasma. Additionally, dissociates Aβ/fibrinogen complex prevents exacerbating Aβ-induced synaptotoxicity mouse organotypic hippocampal cultures. These findings reveal possible protective mechanism by may slow progression