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Lecanemab Blocks the Effects of the Aβ/Fibrinogen Complex on Blood Clots and Synapse Toxicity in Organotypic Culture
Pradeep Kumar Singh1, Elisa Nicoloso Simoes Pires1, Zu-Lin Chen1
1Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY, 10065.
Insights
Lecanemab, an Alzheimer's disease (AD) therapy, blocks harmful interactions between amyloid-beta (Aβ) and fibrinogen. This mechanism may protect against Aβ-induced neuroinflammation and vascular dysfunction in AD patients.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Alzheimer's disease (AD) involves brain protein aggregates, neuroinflammation, and vascular issues.
- A compromised blood-brain barrier in AD allows blood proteins like fibrinogen to enter the brain.
- Fibrinogen exacerbates AD pathology by interacting with amyloid-beta (Aβ) peptides, worsening clotting and cerebrovascular problems.
Approach:
- Investigated lecanemab's effect on Aβ/fibrinogen interactions in vitro and in human plasma.
- Assessed lecanemab's ability to normalize fibrinolysis and clot abnormalities.
- Evaluated lecanemab's impact on Aβ/fibrinogen complex dissociation and Aβ-induced synaptotoxicity in mouse brain cultures.
Key Points:
- Lecanemab inhibits fibrinogen binding to Aβ protofibrils.
- The antibody normalizes Aβ/fibrinogen-mediated fibrinolysis and clot abnormalities.
- Lecanemab dissociates the Aβ/fibrinogen complex, mitigating Aβ-induced synaptotoxicity.
Conclusions:
- Lecanemab may offer neuroprotection by blocking detrimental Aβ-fibrinogen interactions.
- This mechanism provides a potential explanation for lecanemab's therapeutic effects in slowing AD progression.
- Findings highlight the role of vascular factors and their modulation in Alzheimer's disease treatment.
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, shows promising results in facilitating reduction of Aβ from the brain and slowing cognitive decline. Here we show that lecanemab blocks fibrinogen's binding to Aβ protofibrils, normalizing 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.
