Summary Alzheimer's disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the β-amyloid peptide (Aβ) is a critical factor in this disease, we examined its relationship to fibrin clot formation in AD. In vitro and in vivo experiments showed that fibrin clots formed in the presence of Aβ are structurally abnormal and resistant to degradation. Fibrin(ogen) was observed in blood vessels positive for amyloid in mouse and human AD samples, and intravital brain imaging of clot formation and dissolution revealed abnormal thrombosis and fibrinolysis in AD mice. Moreover, depletion of fibrinogen lessened cerebral amyloid angiopathy pathology and reduced cognitive impairment in AD mice. These experiments suggest that one important contribution of Aβ to AD is via its effects on fibrin clots, implicating fibrin(ogen) as a potential critical factor in this disease.
Increasing evidence supports a vascular contribution to Alzheimer's disease (AD), but a direct connection between AD and the circulatory system has not been established. Previous work has shown that blood clots formed in the presence of the β-amyloid peptide (Aβ), which has been implicated in AD, have an abnormal structure and are resistant to degradation in vitro and in vivo. In the present study, we show that Aβ specifically interacts with fibrinogen with a K d of 26.3 ± 6.7 nM, that the binding site is located near the C terminus of the fibrinogen β-chain, and that the binding causes fibrinogen to oligomerize. These results suggest that the interaction between Aβ and fibrinogen modifies fibrinogen's structure, which may then lead to abnormal fibrin clot formation. Overall, our study indicates that the interaction between Aβ and fibrinogen may be an important contributor to the vascular abnormalities found in AD. A lzheimer's disease (AD) is a neurodegenerative disorder that leads to progressive cognitive decline and subsequent death. Effective long-term treatments and preventive measures are not available, and new therapeutic targets are needed. Substantial evidence indicates that the β-amyloid (Aβ) peptide, which is derived from the Aβ precursor protein (APP), is involved in AD (1-3). Aβ is soluble in its monomeric or oligomeric states, but can aggregate into fibrils and deposit as extracellular plaques in the brain parenchyma. However, the severity of dementia does not correlate well with the amount of extracellular amyloid plaques and the mechanism by which Aβ causes neurodegeneration is still unclear (4).Aβ can also accumulate in brain blood vessels, a condition known as cerebral amyloid angiopathy (CAA). CAA is characterized by deposition of Aβ within cerebral vessels, resulting in degenerative vascular changes (5-7). In mouse models of AD, endothelial cells in CAA vessels show early dysfunction, which reduces their response to vasodilators (8) and impairs the regulation of blood flow (9, 10). Many patients with AD present vascular symptoms, including altered cerebral blood flow, damaged cerebral vasculature, and abnormal hemostasis (11). Cerebral blood flow is reduced and many vascular defects are present in patients with AD (12). Vascular diseases such as atherosclerosis correlate in severity with dementia and other symptoms of sporadic AD (13-15). Vascular abnormalities could therefore play an important role in AD, but a direct connection remains unknown.Fibrinogen is the primary protein component of blood clots. It is 45 nm in length with identical globular domains at each end, which are connected by rod-like strands. It is composed of three pairs of polypeptide chains, designated Aα, Bβ, and γ, which are connected by disulfide bonds (16). When fibrinopeptides A and B of fibrinogen are cleaved by the serine protease thrombin, fibrinogen noncovalently polymerizes to form protofibrils, which then branch to form an insoluble fibrin clot. This clot network forms a mesh around platelets to impede blood fl...
Alzheimer disease is characterized by the presence of increased levels of the -amyloid peptide (A) in the brain parenchyma and cerebral blood vessels. This accumulated A can bind to fibrin(ogen) and render fibrin clots more resistant to degradation. Here, we demonstrate that A 42 specifically binds to fibrin and induces a tighter fibrin network characterized by thinner fibers and increased resistance to lysis. However, A 42 -induced structural changes cannot be the sole mechanism of delayed lysis because A overlaid on normal preformed clots also binds to fibrin and delays lysis without altering clot structure. In this regard, we show that A interferes with the binding of plasminogen to fibrin, which could impair plasmin generation and fibrin degradation. Indeed, plasmin generation by tissue plasminogen activator (tPA), but not streptokinase, is slowed in fibrin clots containing A 42 , and clot lysis by plasmin, but not trypsin, is IntroductionCerebrovascular dysfunction has been implicated as an early event in Alzheimer disease (AD) progression, 1-4 but the origins and mechanisms of vascular dysfunction in AD are not clear. The -amyloid peptide (A) accumulates in the brain parenchyma and blood vessel walls of AD patients and has been genetically and clinically linked to AD. We have previously shown that fibrinogen, the main protein component of blood clots, can bind A 42 (henceforth designated A) specifically with a K d of 26.3 Ϯ 6.7nM. 5 We also found that fibrin clots formed in the presence of A are structurally altered and more resistant to fibrinolysis than normal clots. 6 However, the mechanism by which A-fibrin(ogen) binding delays fibrin clot lysis has not been defined.Fibrin clot lysis is mediated by plasmin, a serine protease that cleaves the fibrin network at specific sites. Plasmin is derived from plasminogen by tissue plasminogen activator (tPA) in the presence of fibrin, which itself enhances the rate of the reaction. One fibrin site initially involved in plasminogen activation by tPA includes residues 148-160 on the A␣-chain (reviewed by Medved and Nieuwewnhuizen 7 ). This site becomes exposed and available for plasminogen binding after the conversion of fibrinogen to fibrin, 8 but could remain hidden if clots are formed in the presence of A, leading to delayed clot lysis. This hypothesis is derived from our finding that A binds the fibrinogen -chain near the -hole, 5 which is in close spatial proximity to residues 148-160 of the A␣-chain. 9 Another potential explanation for delayed clot lysis is based on the relationship between fibrin structure and its susceptibility to fibrinolysis. Tighter fibrin networks composed of thin fibers are degraded less efficiently by plasmin than those composed of thick fibers 10-13 because: (1) there are more fibers to be cleaved, 11,14 requiring plasmin to detach from and move between fibers more frequently 15 ; and (2) decreased network porosity of tighter fibrin networks results in impeded diffusion of fibrinolytic enzymes throughout the clot (...
Alzheimer's disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which likely contributes to disease via multiple mechanisms. Increasing evidence implicates inflammation in AD, the origins of which are not completely understood. We investigated whether circulating Aβ could initiate inflammation in AD via the plasma contact activation system. This proteolytic cascade is triggered by the activation of the plasma protein factor XII (FXII) and leads to kallikrein-mediated cleavage of high molecular-weight kininogen (HK) and release of proinflammatory bradykinin. Aβ has been shown to promote FXII-dependent cleavage of HK in vitro. In addition, increased cleavage of HK has been found in the cerebrospinal fluid of patients with AD. Here, we show increased activation of FXII, kallikrein activity, and HK cleavage in AD patient plasma. Increased contact system activation is also observed in AD mouse model plasma and in plasma from wild-type mice i.v. injected with Aβ42. Our results demonstrate that Aβ42-mediated contact system activation can occur in the AD circulation and suggest new pathogenic mechanisms, diagnostic tests, and therapies for AD.Alzheimer's disease | factor XII | high molecular-weight kininogen | plasma kallikrein A lzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex and still poorly defined etiology. Although multiple factors are likely involved in AD onset and development, a growing body of evidence implicates both neuroinflammation and peripheral inflammation in the disease (1-3). Pathways capable of triggering inflammatory processes are therefore of particular interest to AD etiology and pathogenesis. One such pathway is the contact activation system, which is initiated when the plasma protein factor XII (FXII) is exposed to negatively charged surfaces (contact activation). Contact-activated FXII (FXIIa) triggers plasma kallikrein-mediated cleavage of high molecular-weight kininogen (HK) to release bradykinin, which promotes inflammatory processes including increased bloodbrain barrier permeability, edema, and cytokine expression (4) via interaction with receptors B 1 and B 2 (5). In AD, a possible surface for FXII activation could be the AD-associated peptide beta-amyloid (Aβ), which has been shown to stimulate FXII-dependent plasma kallikrein activity (6, 7) and kallikrein-mediated HK cleavage (6, 8) in vitro.Although the contact activation system is primarily thought to function in the circulation, there is evidence for its dysregulation in AD brain tissue: FXII is found in Aβ plaques (9), increased plasma kallikrein activity is observed in the AD brain parenchyma (10), and elevated levels of cleaved HK are found in cerebrospinal fluid (CSF) of patients with AD (11). To our knowledge, FXII activation and HK cleavage in the periphery of AD patients have not been demonstrated.Here, we show increased levels of FXIIa, HK cleavage, and kallikrein activity in the plasma of AD patients compared with nondemented (ND) control plasma. Furthermore, plasma...
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 (CAA) 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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