Breaking boundaries—coagulation and fibrinolysis at the neurovascular interface

Bardehle, Sophia; Rafalski, Victoria A.; Akassoglou, Katerina

doi:10.3389/fncel.2015.00354

Cited by 62 publications

(71 citation statements)

References 108 publications

(154 reference statements)

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“…These results underline the strong links that exist among the coagulation cascade, neuroinflammation, and neuronal damage (see figure). 3 Nevertheless, the nature of the fibrin deposits found in this study (ie, whether they are intravascular clots, perivascular deposits, and/or actual parenchymal deposits associated with Ab) cannot be evaluated from the data. Future studies are also warranted to determine the exact temporal effects of FXII and the downstream members of the coagulation cascade on the specific components of the neuronal circuitry.…”

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confidence: 85%

“…2 Clinically, cGVHD is characterized mainly by scleroderma, BO, and oral lichen planus-like lesions. [2][3][4] There is significant morbidity and mortality associated with cGVHD; in particular, patients with BO have a 5-year mortality rate of 41%. These poor results underscore the need to develop effective anti-cGVHD therapies.…”

mentioning

confidence: 99%

“…4,5 Fibrin is, therefore, implicated in the pathogenesis of various neurological diseases with an inflammatory component, including vasculitis, stroke, brain trauma, and multiple sclerosis. 3 Importantly, fibrin has a central role in AD pathogenesis by promoting neurodegeneration and neuroinflammation and impairing cognitive function. [6][7][8] Indeed,…”

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confidence: 99%

“…Multiple studies in humans and experimental animal models have shown that fibrin is causally linked with neuroinflammation. 3 Primarily because of its unique binding to specific integrin receptors on inflammatory cells, fibrin mediates, controls, and sometimes triggers neuroinflammation. 4,5 Fibrin is, therefore, implicated in the pathogenesis of various neurological diseases with an inflammatory component, including vasculitis, stroke, brain trauma, and multiple sclerosis.…”

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confidence: 99%

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Alzheimer disease makes new blood contacts

Merlini

Akassoglou

2017

Blood

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In this issue of Blood, Chen and colleagues demonstrate an unanticipated role for the contact system in a murine model of Alzheimer disease (AD). The study bolsters the key role of vascular dysfunction in AD by identifying factor XII (FXII) activation as a new molecular player in AD pathogenesis through mechanisms linked to cerebral fibrin deposition, neuroinflammation, and neuronal damage. In their study, Chen et al further elucidated the role of FXII in AD pathogenesis. FXII drives the contact system, which initiates procoagulant and proinflammatory pathways by activating FXI and plasma prekallikrein (PPK), respectively. Previous elegant studies by the authors showed that the FXII-mediated contact pathway is activated in AD patients by Ab, thereby stimulating the conversion of fibrinogen to the inflammatory fibrin.7 Given the dual procoagulant and proinflammatory roles of FXII, the authors argued that this system could be activated at early AD stages. Using the TgCRND8 AD mouse model harboring three mutations in the amyloid precursor protein pertinent to Ab pathology, the authors found a temporal correlation between activation of the inflammatory branch of the contact pathway and the onset of neuroinflammation, as indicated by increased cleavage of high-molecular-weight plasma kininogen (HK). Strikingly, by depleting FXII, the authors showed that plasma HK cleavage, neuroinflammation, cerebral fibrin deposition, and neurodegeneration were reduced and cognitive function was improved in the mice studied. These results provide further evidence for the role of the coagulation cascade in AD and suggest that individual members of the cascade, including FXII, may be potential therapeutic AD targets. Given the synergy between neuroinflammation and vascular pathology in AD pathogenesis, this study raises the important question how they are linked mechanistically. The authors asked first whether a temporal correlation exists between HK cleavage/contact system activation and AD progression. By measuring plasma intact HK (HKi) levels in TgCRND8 mice at different disease stages, they found that these were already decreased in 3-month-old mice, indicating increased HK cleavage starting at early Ab pathology. These actions were accompanied by increased astrocytosis and microgliosis, although the latter became significant only at 6 months of age. Whether this differential temporal regulation between the HK and microgliosis data indicates that the temporal correlation between changes in HK cleavage and onset of microglia activation is actually less pronounced than suggested by the authors or is due to the authors' use of Iba-1 instead of the more sensitive CD11b as a marker of microglia activation in these specific experiments is unclear. Interestingly, by depleting plasma FXII with antisense oligonucleotide (ASO)-mediated messenger RNA knockdown, levels of both HKi and PPK in the treated transgenic mice were similar to those in the wild-type controls. These findings indicate that FXII activation indeed mediates the proinflamm...

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confidence: 85%

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Alzheimer disease makes new blood contacts

Merlini

Akassoglou

2017

Blood

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“…Additionally, fibrin depletion delays the onset of neuroinflammation and demyelination in transgenic mouse models of MS 231 , and treatment with fibrin induced M1-type activation and induction of antigen-presenting genes in both primary microglia and bone marrow-derived macrophages 232 . The role of coagulation and fibrinolysis proteins on development of brain pathology in MS has been reviewed elsewhere 233 .…”

Section: Bbb Breakdown and Neurodegenerationmentioning

confidence: 99%

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

2018

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The blood–brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts, and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation, and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells, and microbial pathogens, and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain, post-mortem tissue and biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery, and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting BBB are presented.

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Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex

Yates

Esiri

Palace

et al. 2017

Annals of Neurology

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For the first time, we provide unequivocal evidence that fibrin(ogen) is extensively deposited in progressive MS motor cortex, where regulation of fibrinolysis appears perturbed. Progressive MS cases with severe fibrin(ogen) deposition have significantly reduced neuronal density. Future studies are needed to elucidate the provenance and putative neurotoxicity of fibrin(ogen), and its potential impact on clinical disability. Ann Neurol 2017;82:259-270.

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Breaking boundaries—coagulation and fibrinolysis at the neurovascular interface

Cited by 62 publications

References 108 publications

Alzheimer disease makes new blood contacts

Alzheimer disease makes new blood contacts

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex

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