Daria Zamolodchikov

Fibrinogen and β-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the beta-amyloid peptide (Abeta) 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 Abeta 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 Abeta to AD is via its effects on fibrin clots, implicating fibrin(ogen) as a potential critical factor in this disease.

Alzheimer's disease peptide β-amyloid interacts with fibrinogen and induces its oligomerization

Increasing evidence supports a vascular contribution to Alzheimers 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 Kd 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 fibrinogens 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.

Fibrinogen and Altered Hemostasis in Alzheimer's Disease

Alzheimers 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.

Aβ delays fibrin clot lysis by altering fibrin structure and attenuating plasminogen binding to fibrin

Alzheimer disease is characterized by the presence of increased levels of the β-amyloid peptide (Aβ) in the brain parenchyma and cerebral blood vessels. This accumulated Aβ can bind to fibrin(ogen) and render fibrin clots more resistant to degradation. Here, we demonstrate that Aβ(42) specifically binds to fibrin and induces a tighter fibrin network characterized by thinner fibers and increased resistance to lysis. However, Aβ(42)-induced structural changes cannot be the sole mechanism of delayed lysis because Aβ overlaid on normal preformed clots also binds to fibrin and delays lysis without altering clot structure. In this regard, we show that Aβ 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 Aβ(42), and clot lysis by plasmin, but not trypsin, is delayed. Notably, plasmin and tPA activities, as well as tPA-dependent generation of plasmin in solution, are not decreased in the presence of Aβ(42). Our results indicate the existence of 2 mechanisms of Aβ(42) involvement in delayed fibrinolysis: (1) through the induction of a tighter fibrin network composed of thinner fibers, and (2) through inhibition of plasmin(ogen)-fibrin binding.

A novel Aβ-fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer’s disease mice

Pharmacological disruption of the interaction between fibrinogen and β-amyloid reduces vascular amyloid deposition and improves cognition in a mouse model of Alzheimer’s disease.

Activation of the factor XII-driven contact system in Alzheimer’s disease patient and mouse model plasma

Significance Alzheimer’s disease (AD) is a growing public health problem, in part because there are no effective therapies. Major roadblocks to the treatment of AD are the lack of adequate diagnostic tools and the absence of viable therapeutic targets. It is now clear that AD is characterized by inflammation. Our results indicate that AD patients and mouse models have increased activation of a set of proteins known as the contact activation system in their circulation. We also demonstrate that the AD-related peptide Aβ can initiate activation of this system in the circulation of animal models. Because the contact activation system contributes to inflammation, our results suggest new pathogenic mechanisms, diagnostic tests, and therapeutic targets for AD. 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.

The Alzheimer's disease peptide β-amyloid promotes thrombin generation through activation of coagulation factor XII.

Essentials How the Alzheimers disease (AD) peptide β‐amyloid (Aβ) disrupts neuronal function in the disease is unclear. Factor (F) XII initiates blood clotting via FXI, and thrombosis has been implicated in AD. Aβ triggers FXII‐dependent FXI and thrombin activation, evidence of which is seen in AD plasma. Aβ‐triggered clotting could contribute to neuronal dysfunction in AD and be a novel therapeutic target.

A possible new role for Aβ in vascular and inflammatory dysfunction in Alzheimer's disease

Alzheimers disease (AD) is often characterized by vascular pathology, a procoagulant state, and chronic inflammation. The mechanisms behind these abnormalities in AD are not clear. Here, we review evidence for the role of the AD-associated peptide Aβ in promoting inflammation and thrombosis in AD via its interaction with the circulating proteins factor XII and fibrinogen.

Biochemical and structural analysis of the interaction between β-amyloid and fibrinogen.

The majority of patients with Alzheimer disease (AD) suffer from impaired cerebral circulation. Accumulating evidence suggests that fibrinogen, the main protein component of blood clots, plays an important role in this circulatory dysfunction in AD. Fibrinogen interacts with β-amyloid (Aβ), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition is found in the brains of AD patients and mouse models. In this study, we investigated the biochemical and structural details of the Aβ-fibrinogen interaction. We identified the central region of Aβ42 as the most critical region for the interaction, which can be inhibited by specific antibodies against the central region of Aβ and by naturally occurring p3 peptides, Aβ17-40 and Aβ17-42. X-ray crystallographic analysis revealed that Aβ42 binding to fragment D of fibrinogen induced a structural change in the C-terminal region of the fibrinogen β-chain (β384-393). Furthermore, we identified an additional Aβ-binding site within the αC region of fibrinogen. Aβ binding to this αC region blocked plasmin-mediated fibrin cleavage at this site, resulting in the generation of increased levels of a plasmin-resistant fibrin degradation fragment. Overall, our study elucidates the Aβ-fibrinogen interaction and clarifies the mechanism by which Aβ-fibrinogen binding delays fibrinolysis by plasmin. These results may facilitate the development of effective therapeutics against the Aβ-fibrinogen interaction to treat cerebrovascular abnormalities in AD.

Interactions of β-amyloid peptide with fibrinogen and coagulation factor Xii may contribute to Alzheimer's disease

Purpose of review To review the evidence that the Alzheimer peptide &bgr;-amyloid interacts with the blood coagulation system and influences the pathophysiology of the disease. Recent findings &bgr;-amyloid can interact with fibrinogen and blood coagulation factor XII and trigger ischemia and inflammation. Summary &bgr;-amyloid interacts with fibrinogen and factor XII. These interactions can lead to increased clotting, abnormal clot formation, persistent fibrin deposition, and generation of proinflammatory molecules. These events can damage neurons and could contribute to the cognitive decline in Alzheimers disease patients.