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Hemostasis components in cerebral amyloid angiopathy and Alzheimer’s disease

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Abstract

Increased cerebrovascular amyloid-β (Aβ) deposition represents the main pathogenic mechanisms characterizing Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Whereas an increasing number of studies define the contribution of fibrin(ogen) to neurodegeneration, how other hemostasis factors might be pleiotropically involved in the AD and CAA remains overlooked. Although traditionally regarded as pertaining to hemostasis, these proteins are also modulators of inflammation and angiogenesis, and exert cytoprotective functions. This review discusses the contribution of hemostasis components to Aβ cerebrovascular deposition, which settle the way to endothelial and blood-brain barrier dysfunction, vessel fragility, cerebral bleeding, and the associated cognitive changes. From the primary hemostasis, the process that refers to platelet aggregation, we discuss evidence regarding the von Willebrand factor (vWF) and its regulator ADAMTS13. Then, from the secondary hemostasis, we focus on tissue factor, which triggers the extrinsic coagulation cascade, and on the main inhibitors of coagulation, i.e., tissue factor pathway inhibitor (TFPI), and the components of protein C pathway. Last, from the tertiary hemostasis, we discuss evidence on FXIII, involved in fibrin cross-linking, and on components of fibrinolysis, including tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and its receptor uPA(R), and plasminogen activator inhibitor-1 (PAI-1). Increased knowledge on contributors of Aβ-related disease progression may favor new therapeutic approaches for early modifiable risk factors.

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  1. CAA and AD Translational Research and Biomarkers Laboratory, School of Medicine and Surgery, University of Milano – Bicocca, Via Cadore 48, 20900, Monza, Italy

    Nicole Ziliotto & Fabrizio Piazza

  2. Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy

    Francesco Bernardi

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Nicole Ziliotto contributed to the study concept and design, drafting the work, and critical revision of the manuscript for important intellectual content. Francesco Bernardi and Fabrizio Piazza contributed to the critical revision of the manuscript for important intellectual content. All the authors read and approved the final manuscript.

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NZ has nothing to disclose.

FB reports grants from Bayer and Pfizer on coagulation issues but outside the submitted work.

FP reports grants from the Alzheimer’s Association (ModelCAA Research Grant - AARG-18-561699); Fondazione Cariplo (biomarkARIA Research Project - 2015-0820), and the Canadian Institute of Health Research, outside the submitted work. FP received personal and Institutional fees and served as Scientific Academic Consultant and Advisor for Hoffmann La-Roche and Biogen, outside the submitted work. FP is the inventor (without ownership) of a patent for a method and kit for the Aβ-autoantibody test, outside the submitted work.

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Ziliotto, N., Bernardi, F. & Piazza, F. Hemostasis components in cerebral amyloid angiopathy and Alzheimer’s disease. Neurol Sci 42, 3177–3188 (2021). https://doi.org/10.1007/s10072-021-05327-7

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