Fibrinogen and Altered Hemostasis in Alzheimer's Disease

Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 08/2012; 32(3). DOI: 10.3233/JAD-2012-120820
Source: PubMed


Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques, tau tangles, brain atrophy, and vascular pathology. Vascular defects include cerebrovascular dysfunction, decreased cerebral blood flow, and blood brain barrier (BBB) disruption, among others. Here, we review the evidence that links Aβ with the vascular pathology present in AD, with a specific focus on the hemostatic system and the clotting protein fibrinogen. Fibrinogen is normally found circulating in blood, but in AD it deposits with Aβ in the brain parenchyma and cerebral blood vessels. We found that Aβ and fibrin(ogen) interact, and their binding leads to increased fibrinogen aggregation, Aβ fibrillization, and the formation of degradation-resistant fibrin clots. Decreasing fibrinogen levels not only lessens cerebral amyloid angiopathy and BBB permeability, but it also reduces microglial activation and improves cognitive performance in AD mouse models. Moreover, a prothrombotic state in AD is evidenced by increased clot formation, decreased fibrinolysis, and elevated levels of coagulation factors and activated platelets. Abnormal deposition and persistence of fibrin(ogen) in AD may result from Aβ-fibrin(ogen) binding and altered hemostasis and could thus contribute to Aβ deposition, decreased cerebral blood flow, exacerbated neuroinflammation, and eventual neurodegeneration. Blocking the interaction between fibrin(ogen) and Aβ may be a promising therapeutic target for AD.

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Available from: Marta Cortes-Canteli, Jun 11, 2014
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    • "In addition to extravascular disturbance to the brain, cerebrovascular dysfunction was also presented in AD brains, including cerebral amyloid angiopathy where amyloid-b (Ab) is deposited as plaques in the blood vessels. Fibrinogen bound to Ab is not efficiently cleared from the brain because hemostasis is altered in AD[14]. Because the brain needs a smooth supply of oxygen and glucose, as it lacks long-term energy stores, the plaques damage the cerebrovascular structure and compromise its function, thereby inducing cerebral hypoperfusion. "
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    ABSTRACT: The relationship of C-reactive protein (CRP) to cognition in the older old group (≥75 years) has recently been found positive on both sides of the Atlantic. We hypothesized that higher levels of CRP and fibrinogen are related to worse episodic memory throughout later life (≥50 years).
    Full-text · Article · Dec 2015
    • "Fibrinogen has emerged as a putative target against vascular and A pathologies in AD since it has been demonstrated that blocking its activity may reduce A deposition in brain parenchyma and vessels, as well as may decrease the inflammatory processes linked to AD progression [1]. In line with these previous findings, here we provide evidence of the therapeutic properties at the cognitive level of the fibrinogen-derived peptide Fib 377−395 in an AD experimental model, the double transgenic APP/PS1 mice. "
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    ABSTRACT: Fibrinogen has emerged as a promising therapeutic target against Alzheimer's disease because of its dual role in altered vascular function and amyloid-β aggregation. Here we provide evidence regarding cognitive improvement and reduction of brain parenchyma amyloid-β deposition in AβPP/PS1 mice after treatment for one month with the fibrinogen-blocking peptide Fibγ377-395. No alteration in glial response or other neuroinflammatory markers was observed in the cortex of treated animals. Considering these results and the fact that Fibγ377-395 does not affect coagulation function, this peptide could be considered as a promising and safe candidate for chronic treatment of Alzheimer's disease.
    No preview · Article · Sep 2015 · Journal of Alzheimer's disease: JAD
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    • "Under normal circumstances, fibrinogen is excluded from the brain by the BBB, but due to BBB dysfunction it can be found co-localized with A␤ deposit in AD brain [75]. A␤ can bind fibrin(ogen) directly, promoting the deposition of A␤ in AD brain parenchyma and vessels, leading to formation of abnormal fibrin clots and cerebrovascular dysfunction [75]. Here levels of fibrinogen ␤-chain were lower in MCI but higher in AD. "
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    ABSTRACT: To unlock the full potential of disease modifying treatments, it is essential to develop early biomarkers for Alzheimer's disease (AD). For practical reasons, blood-based markers that could provide a signal at the stage of mild cognitive impairment (MCI) or even earlier would be ideal. Using the proteomic approach of isobaric tagging for relative and absolute quantitation (iTRAQ), we compared the plasma protein profiles of MCI, AD, and cognitively normal control subjects from two independent cohorts: the Sydney Memory and Ageing Study (261 MCI subjects, 24 AD subjects, 411 controls) and the Hunter Community Study (180 MCI subjects, 153 controls). The objective was to identify any proteins that are differentially abundant in MCI and AD plasma in both cohorts, since they might be of interest as potential biomarkers, or could help direct future mechanistic studies. Proteins representative of biological processes relevant to AD pathology, such as the complement system, the coagulation cascade, lipid metabolism, and metal and vitamin D and E transport, were found to differ in abundance in MCI. In particular, levels of complement regulators C1 inhibitor and factor H, fibronectin, ceruloplasmin, and vitamin D-binding protein were significantly decreased in MCI participants from both cohorts. Several apolipoproteins, including apolipoprotein AIV, B-100, and H were also significantly decreased in MCI. Most of these proteins have previously been reported as potential biomarkers for AD; however, we show for the first time that a significant decrease in plasma levels of two potential biomarkers (fibronectin and C1 inhibitor) is evident at the MCI stage.
    Full-text · Article · Jan 2015 · Journal of Alzheimer's disease: JAD
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