In this issue of Blood, Zamolodchikov and Strickland examine the association of β-amyloid (Aβ) peptide with fibrin(ogen).1 These findings shed new light on the relationship between Alzheimer disease and cardiovascular disease, as well as on a novel biochemical mechanism regulating clot stability and dissolution.
Alzheimer disease (AD) is a neurodegenerative disorder with still undefined etiology. The prevailing hypothesis that suggests Aβ peptide deposition and accumulation into plaques promotes AD is giving way to a more complex picture that also includes vascular dysfunction. Observations that cardiovascular disease (CVD; stroke, cardiac disease, and atherosclerosis) is an established risk factor for AD (reviewed in de la Torre2 ) lend credence to the hypothesis that these diseases share a common etiology.
Indeed, recent work has identified a likely candidate at the nexus of these disease processes: fibrinogen. Fibrinogen is the protein substrate of the multifaceted procoagulant and proinflammatory enzyme thrombin. Fibrin, the product of thrombin's proteolytic cleavage of fibrinogen, provides biophysical and biochemical support to blood clots, and subsequent degradation of fibrin by plasmin is an essential step in wound healing. Abnormalities in fibrin structure and/or dissolution are correlated with bleeding in hemophilia, as well as a host of thrombotic disorders, including myocardial infarction, ischemic stroke, and venous thromboembolism (reviewed in Wolberg3 ). Previous in vitro and in vivo studies from the Strickland laboratory have shown that Aβ mediates the formation of clots that have altered structure and increased resistance to fibrinolysis.4,5 The co-existence of these 2 features is consistent with prior studies showing that fibrin network structure and fiber diameter directly regulate the rate of fibrinolysis; plasma clots with a dense network of fibers—like those that form in the presence of Aβ—are dissolved at a slower rate than those with an open (coarse) network of fibers.6 Thus, the mechanism correlating Aβ-induced formation of abnormal fibrin structure with delayed fibrinolysis seemed straightforward, and the story could have ended there.
However, Zamolodchikov and Strickland have now taken this investigation one step further. While confirming that Aβ mediates the formation of clots with abnormal structure and resistance to fibrinolysis, they made the intriguing discovery that the abnormal resistance of these clots to fibrinolysis occurs though mechanisms that are independent of the fiber structure.1 Using an elegant combination of turbidity measurements, protein binding assays, and confocal microscopy, the authors show that by binding to the fibrin network Aβ partially blocks the binding of plasminogen to fibrin, thus interfering with fibrin's co-factor ability to co-localize plasminogen and tissue plasminogen activator on the fibrin fiber. The result is reduced plasmin generation. Zamolodchikov and Strickland further show that Aβ also delays the ability of preformed plasmin to degrade the clot, suggesting plasmin binding might also be reduced by Aβ. Hence, these studies suggest 3 independent mechanisms by which Aβ can alter fibrinolysis (see figure). Aβ binding to fibrin(ogen) (1) intercalates into fibrin fibers during formation, promoting the formation of clots with an abnormally dense fiber network; (2) blocks binding of plasminogen to fibrin and therefore fibrin's ability to support plasmin generation; and (3) blocks plasmin-mediated cleavage of fibrin, directly reducing the rate of fibrinolysis. These studies show Aβ can reduce fibrinolysis by associating with the fibrin network either during or after fibrin formation, suggesting that the introduction of Aβ at any point in fibrin's lifespan would have pathologic consequences.
These findings have important implications for AD research. The demonstrated interaction between Aβ and fibrin(ogen) reconciles the leading independent theories that AD results from deposition of Aβ or from other cardiovascular risk factors. Elevated circulating fibrinogen is an established risk factor for both CVD and AD.7-9 Elevated fibrinogen promotes thrombosis in part via increased fibrin network density and increased resistance to lysis10 in CVD and likely AD as well. The finding that in AD, increased fibrin stability can also result from interactions between Aβ and fibrin suggests fibrinogen can participate in multiple, independent pathways in the development of AD. Presumably, increased vascular permeability permits fibrin deposition in the cerebrovasculature and Aβ protects fibrin deposits from degradation, culminating in vascular obstruction and fibrin(ogen)-mediated inflammation in the brain. The current findings strongly support continued studies investigating the connection(s) between vascular dysfunction and fibrin(ogen) deposition. Moreover, blocking the binding of Aβ to fibrin by pharmacologically targeting Aβ may enable plasmin(ogen) binding to the network and permit endogenous fibrinolytic mechanisms to clear fibrin deposits. By not targeting the fibrinolytic pathway directly, this “indirect” approach may be expected to have low risk of bleeding.
These findings also have important implications for understanding the contributions of fibrinogen to hemostasis and thrombosis. Other proteins besides Aβ, including fibronectin (reviewed in Wolberg3 ), have been shown to both alter fibrin structure and decrease the rate of fibrinolysis. These two clot properties also co-exist in many thrombotic diseases. Until now, findings of abnormal fibrin network structure were considered sufficient to explain differences in fibrinolysis. However, the current study puts an end to this biologic hand-waving because it shows that changes in fibrin network structure may not be sufficient to explain abnormal fibrinolysis in all cases. Could as-yet-unidentified molecules circulating in disease states directly alter binding of fibrinolytic enzymes to fibrin in other thrombotic diseases? Experiments to explicitly measure binding of tissue plasminogen activator and plasmin(ogen) to the fibrin network in cases of reduced fibrinolysis may reveal such novel molecules. As such, this work establishes a new standard for future studies of mechanisms regulating clot structure and stability.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
National Institutes of Health