Fibrinogen and Altered Hemostasis in Alzheimer's Disease.
ABSTRACT 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.
- SourceAvailable from: hematologylibrary.orgBlood 09/1978; 52(2):453-66. · 9.06 Impact Factor
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ABSTRACT: Mast cells, strategically located in the vicinity of blood vessels, are multifunctional effector cells participating in the modulation of various inflammatory and cardiovascular disease processes by actively releasing a wide variety of vasoactive mediators. These cells have also been implicated in the regulation of thrombosis and the development and progression of atherosclerosis. By expressing enzymatically active tissue type-plasminogen activator (t-PA), human mast cells (MC) might play a role in endogenous fibrinolysis and extracellular matrix remodelling--both processes that are essential in the pathogenesis of cardiovascular disorders. However, when treated with the anaphylotoxin C5a, mast cells express the PA inhibitor 1 (PAI-1) in excess over t-PA. In context with studies suggesting a role for mast cells and components of the complement system in the development of cardiovascular disease our results lead to the hypothesis that mast cells by producing t-PA in a resting state and by expressingPAI-1 when activated by C5a might participate in the modulation of the balance between proteases and protease inhibitors regulating tissue injury and repair in these disease processes. In addition, C5a might upregulate PAI-1 in mast cells to prevent its own in activation by plasmin in an autocrine or paracrine fashion.Pathophysiology of Haemostasis and Thrombosis 01/2003; 33(5-6):438-41. · 2.23 Impact Factor
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ABSTRACT: Cerebrovascular disease and Alzheimer disease are common diseases of aging and frequently coexist in the same brain. Accumulating evidence suggests that the presence of brain infarction, including silent infarction, influences the course of Alzheimer disease. Conversely, there is evidence that beta-amyloid can impair blood vessel function. Vascular beta-amyloid deposition, also known as cerebral amyloid angiopathy, is associated with vascular dysfunction in animal and human studies. Alzheimer disease is associated with morphological changes in capillary networks, and soluble beta-amyloid produces abnormal vascular responses to physiological and pharmacological stimuli. In this review, we discuss current evidence linking beta-amyloid metabolism with vascular function and morphological changes in animals and humans.Stroke 06/2009; 40(7):2601-6. · 6.16 Impact Factor