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

ABSTRACT: Essentials How the Alzheimer's disease (AD) peptide ?-amyloid (A?) disrupts neuronal function in the disease is unclear. Factor (F) XII initiates blood clotting via FXI, and thrombosis has been implicated in AD. A? triggers FXII-dependent FXI and thrombin activation, evidence of which is seen in AD plasma. A?-triggered clotting could contribute to neuronal dysfunction in AD and be a novel therapeutic target.Background ?-Amyloid (A?) is a key pathologic element in Alzheimer's disease (AD), but the mechanisms by which it disrupts neuronal function in vivo are not completely understood. AD is characterized by a prothrombotic state, which could contribute to neuronal dysfunction by affecting cerebral blood flow and inducing inflammation. The plasma protein factor XII triggers clot formation via the intrinsic coagulation cascade, and has been implicated in thrombosis. Objectives To investigate the potential for A? to contribute to a prothrombotic state. Methods and results We show that A? activates FXII, resulting in FXI activation and thrombin generation in human plasma, thereby establishing A? as a possible driver of prothrombotic states. We provide evidence for this process in AD by demonstrating decreased levels of FXI and its inhibitor C1 esterase inhibitor in AD patient plasma, suggesting chronic activation, inhibition and clearance of FXI in AD. Activation of the intrinsic coagulation pathway in AD is further supported by elevated fibrin levels in AD patient plasma. Conclusions The ability of A? to promote coagulation via the FXII-driven contact system identifies new mechanisms by which it could contribute to neuronal dysfunction and suggests potential new therapeutic targets in AD.

SUBMITTER: Zamolodchikov D

PROVIDER: S-EPMC4870142 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Zamolodchikov D D Renné T T Strickland S S

Journal of thrombosis and haemostasis : JTH 20160229 5

<h4>Unlabelled</h4>Essentials How the Alzheimer's 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.<h4>Summary</h4>Background β-Amyloid (Aβ) is a key pathologic element ...[more]

PMID: 26613657

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Project description:BackgroundFactor XII (FXII) activation initiates the intrinsic (contact) coagulation pathway. It has been recently suggested that FXII could act as an autoimmunity mediator in multiple sclerosis (MS). FXII depositions nearby dentritic cells were detected in the central nervous system of MS patients and increased FXII activity has been reported in plasma of relapsing remitting and secondary progressive MS patients. FXII inhibition has been proposed to treat MS.ObjectiveTo investigate in MS patients multiple FXII-related variables, including the circulating amount of protein, its pro-coagulant function, and their variation over time. To explore kinetic activation features of FXII in thrombin generation (TG).MethodsIn plasma from 74 MS patients and 49 healthy subjects (HS), FXII procoagulant activity (FXII:c) and FXII protein (FXII:Ag) levels were assessed. Their ratio (FXII:ratio) values were derived. Intrinsic TG was evaluated by different triggers.ResultsHigher FXII:Ag levels (p = 0.003) and lower FXII:ratio (p < 0.001) were detected in MS patients compared with HS. FXII variables were highly correlated over four time points, which supports investigation of FXII contribution to disease phenotype and progression. A significant difference over time was detected for FXII:c (p = 0.031). In patients selected for the lowest FXII:ratio, TG triggered by ellagic acid showed a trend in lower endogenous thrombin potential (ETP) in MS patients compared with HS (p = 0.042). Intrinsic triggering of TG by nucleic acid addition produced longer time parameters in patients than in HS and substantially increased ETP in MS patients (p = 0.004) and TG peak height in HS (p = 0.008). Coherently, lower FXII:ratio and longer lag time (p = 0.02) and time to peak (p = 0.007) point out a reduced response of FXII to activation in part of MS patients.ConclusionIn MS patients, factor-specific and modified global assays suggest the presence of increased FXII protein level and reduced function within the intrinsic coagulation pathway. These novel findings support further investigation by multiple approaches of FXII contribution to disease phenotype and progression.

Dataset Information

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

Publications

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

Similar Datasets

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