Activation of the Contact System in Cerebrospinal Fluid of Patients with Alzheimer Disease

Bergamaschini, Luigi; Parnetti, Lucilla; Pareyson, Davide; Canziani, Stefania; Cugno, Massimo; Agostoni, A

doi:10.1097/00002093-199806000-00008

Cited by 65 publications

(44 citation statements)

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“…Additionally, we compared levels of cleaved high molecular weight kininogen and FXII in the ND and AD CSF and found that levels were higher in the AD patient samples. These data are in line with previous findings that the contact system is activated in AD CSF 28 (data not shown).…”

Section: Increased Ab40/42 Ratio In Matched Csf Of Ad Patientssupporting

confidence: 94%

Abnormal clotting of the intrinsic/contact pathway in Alzheimer disease patients is related to cognitive ability

et al. 2018

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Key Points• Clot initiation and strength are altered in AD patient plasma and transgenic AD mouse model.• Clotting abnormalities are correlated with the cognitive state of AD patients.Alzheimer disease (AD) is a neurodegenerative disorder characterized by extracellular b-amyloid (Ab) deposition. Although peripheral inflammation and cerebrovascular pathology are reported in AD, there is a lack of plasma biomarkers in this field. Because the contact system is triggered in patient plasma, we hypothesized that the hemostasis profile could be a novel biomarker in AD. Here, we assessed the clotting profile in plasma from AD patients and age-matched controls. Utilizing clinically relevant assays, thromboelastography and activated partial thromboplastin time, we found impaired clot initiation and formation rate in AD patient plasma. These coagulation end points correlated with cerebrospinal fluid neurofilament-light levels and cognition and were more profound in younger AD patients. Ex vivo intrinsic clotting of plasma from AD mice expressing human amyloid precursor protein (APP) was also delayed in an age-dependent manner, suggesting that this phenotype is related to APP, the parent protein of Ab. Further analysis of coagulation factors in human plasma indicated that endogenous inhibitor(s) of factors XII and XI in AD plasma contribute to this delayed clotting. Together, these data suggest that delayed clotting in young AD patients is a novel biomarker and that therapies aimed to correct this phenotype might be beneficial in this patient population. Follow-up studies in additional AD patient cohorts are warranted to further evaluate these findings.

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Section: Increased Ab40/42 Ratio In Matched Csf Of Ad Patientssupporting

confidence: 94%

Abnormal clotting of the intrinsic/contact pathway in Alzheimer disease patients is related to cognitive ability

et al. 2018

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“…The cerebrospinal fluid (CSF) of subjects with AD has been reported to contain elevated FXII activity (8,9). FXII also colocalizes with amyloid plaques in the AD brain (11) and is activated by Aβ in vitro (10).…”

Section: Resultsmentioning

confidence: 99%

“…Based on 3 lines of evidence, we hypothesized that FXII can be activated by misfolded proteins. First, FXII is activated by aggregated amyloid β peptide (Aβ) in vitro, and increased levels of activated FXII are observed in patients with Alzheimer's disease (AD) (8)(9)(10)(11). Second, it has become apparent over recent years that misfolded proteins, in contrast to native proteins, have structural and functional properties similar to those of amyloid (12).…”

Section: Introductionmentioning

confidence: 99%

Misfolded proteins activate Factor XII in humans, leading to kallikrein formation without initiating coagulation

et al. 2008

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When blood is exposed to negatively charged surface materials such as glass, an enzymatic cascade known as the contact system becomes activated. This cascade is initiated by autoactivation of Factor XII and leads to both coagulation (via Factor XI) and an inflammatory response (via the kallikrein-kinin system). However, while Factor XII is important for coagulation in vitro, it is not important for physiological hemostasis, so the physiological role of the contact system remains elusive. Using patient blood samples and isolated proteins, we identified a novel class of Factor XII activators. Factor XII was activated by misfolded protein aggregates that formed by denaturation or by surface adsorption, which specifically led to the activation of the kallikreinkinin system without inducing coagulation. Consistent with this, we found that Factor XII, but not Factor XI, was activated and kallikrein was formed in blood from patients with systemic amyloidosis, a disease marked by the accumulation and deposition of misfolded plasma proteins. These results show that the kallikrein-kinin system can be activated by Factor XII, in a process separate from the coagulation cascade, and point to a protective role for Factor XII following activation by misfolded protein aggregates.

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“…13 HK is also an important member of the plasma kallikrein-kinin system, 14 the activation of which may contribute to the manifestations of disorders such as hereditary angioedema, 15 sepsis, 16 ulcerative colitis, 17 and Alzheimer disease. 18 It would be tempting to assert that the effect of rs710446 on VT risk is mediated by its effect on aPTT levels recently discovered. 4 We also observed a strong association between rs710446 and plasma aPTT levels in MARTHA08 (R 2 ϭ 5.96%, P ϭ 8.74 ϫ 10 Ϫ12 ) and MARTHA10 (R 2 ϭ 9.22%, P ϭ 9.01 ϫ 10 Ϫ11 ), with the rs710446-C allele associated with decreased aPTT levels (supplemental Table 4).…”

Section: Resultsmentioning

confidence: 99%

KNG1 Ile581Thr and susceptibility to venous thrombosis

Morange

Oudot-Mellakh

Cohen

et al. 2011

Blood

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Three single nucleotide polymorphisms (SNPs) were recently found to be associated with activated partial thromboplastin time (aPTT). Because shortened aPTT levels have been observed in patients experiencing venous thrombosis (VT), we investigated the effects of these 3 aPTT-associated SNPs, rs2731672, rs9898, and rs710446, on the risk of VT in a sample of 1110 healthy patients and 1542 patients with VT. Among the 3 tested SNPs, only rs710446 was associated with VT risk; the rs710446-C allele was associated with an increased risk of VT (odds ratio 1.196, 95% confidence interval 1.071-1.336, P ‫؍‬ .0012). This association also was observed in an independent sample of 590 controls and 596 patients (odds ratio 1.171, 95% confidence interval 0.889-1.541, P ‫؍‬ .059). We also confirmed that the rs710446-C allele was associated with decreased aPTT levels, making this nonsynonymous Ile581Thr variant a new genetic risk factor for VT. (Blood. 2011; 117(13):3692-3694)

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Activation of the Contact System in Cerebrospinal Fluid of Patients with Alzheimer Disease

Cited by 65 publications

References 0 publications

Abnormal clotting of the intrinsic/contact pathway in Alzheimer disease patients is related to cognitive ability

Abnormal clotting of the intrinsic/contact pathway in Alzheimer disease patients is related to cognitive ability

Misfolded proteins activate Factor XII in humans, leading to kallikrein formation without initiating coagulation

KNG1 Ile581Thr and susceptibility to venous thrombosis

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