a(CHEBI:Thrombin)
Thrombin is a serine protease that is a well characterized component of the coagulation cascade. It is typically produced and secreted by endothelial cells, including those in the brain in response to hemodynamic injury. PubMed:24027553
Interestingly, phosphorylation of tau also appears to disrupt some thrombin cleavage sites, changing the pattern of cleavage without impeding the thrombin-mediated proteolysis (14, 28). PubMed:24027553
A recent study showed that thrombin is elevated in microvessels isolated from AD brain compared to microvessels from control brain (33). Additionally, thrombin was present in the CSF of AD patients but not in that of controls (33). This is important, as thrombin can act as a neurotoxin by activating intracellular signaling cascades causing neurite retraction and stimulating apoptosis (34–36) PubMed:24027553
A recent study showed that thrombin is elevated in microvessels isolated from AD brain compared to microvessels from control brain (33). Additionally, thrombin was present in the CSF of AD patients but not in that of controls (33). This is important, as thrombin can act as a neurotoxin by activating intracellular signaling cascades causing neurite retraction and stimulating apoptosis (34–36) PubMed:24027553
There are also data to suggest that thrombin may act intracellularly to mediate tau pathology. Thrombin is expressed within neurons and astrocytes in both normal and AD brain (38). In AD brain the staining pattern for thrombin and prothrombin was characteristic of the pattern of NFTs, although these structures were not colabeled with antibodies for tau (38). PubMed:24027553
These RBC microparticles can initiate and propogate thrombin generation (Rubin et al, 2013). PubMed:25307023
However, 6 years later, Heyes and co-workers demonstrated in an experimental study in rats that infusions of thrombin induce DIC accompanied with hemolysis and schistocytosis [89]. PubMed:29956069
However, 6 years later, Heyes and co-workers demonstrated in an experimental study in rats that infusions of thrombin induce DIC accompanied with hemolysis and schistocytosis [89]. PubMed:29956069
However, 6 years later, Heyes and co-workers demonstrated in an experimental study in rats that infusions of thrombin induce DIC accompanied with hemolysis and schistocytosis [89]. PubMed:29956069
Thrombin is a serine protease that is a well characterized component of the coagulation cascade. It is typically produced and secreted by endothelial cells, including those in the brain in response to hemodynamic injury. PubMed:24027553
Evidence supporting a role for thrombin in tau proteolysis came initially from an in vitro study showing that thrombin degraded recombinant full-length tau from the N-terminus yielding a 25-kDa fragment, while preserving the microtubule binding repeat domain (13). PubMed:24027553
Also of importance is understanding the role of non-degradative cleavage in influencing the eventual clearance of tau. Numerous proteases have been shown to proteolyze tau including aminopeptidases (10–12), thrombin (13–15), human high temperature requirement serine protease A1 (HTRA1) (16), calpain (17–20), and caspases (21–24). PubMed:24027553
A recent study showed that thrombin is elevated in microvessels isolated from AD brain compared to microvessels from control brain (33). Additionally, thrombin was present in the CSF of AD patients but not in that of controls (33). This is important, as thrombin can act as a neurotoxin by activating intracellular signaling cascades causing neurite retraction and stimulating apoptosis (34–36) PubMed:24027553
A recent study showed that thrombin is elevated in microvessels isolated from AD brain compared to microvessels from control brain (33). Additionally, thrombin was present in the CSF of AD patients but not in that of controls (33). This is important, as thrombin can act as a neurotoxin by activating intracellular signaling cascades causing neurite retraction and stimulating apoptosis (34–36) PubMed:24027553
Thrombin may also be influencing tau pathology, as treatment of immortalized hippocampal neuronal cells (HT22 cells) with thrombin resulted in the formation of thioflavin-S positive tau aggregates within 24 h, followed by an increase in cell death at 72 h (37). PubMed:24027553
Thrombin may also be influencing tau pathology, as treatment of immortalized hippocampal neuronal cells (HT22 cells) with thrombin resulted in the formation of thioflavin-S positive tau aggregates within 24 h, followed by an increase in cell death at 72 h (37). PubMed:24027553
There are also data to suggest that thrombin may act intracellularly to mediate tau pathology. Thrombin is expressed within neurons and astrocytes in both normal and AD brain (38). In AD brain the staining pattern for thrombin and prothrombin was characteristic of the pattern of NFTs, although these structures were not colabeled with antibodies for tau (38). PubMed:24027553
Evidence supporting a role for thrombin in tau proteolysis came initially from an in vitro study showing that thrombin degraded recombinant full-length tau from the N-terminus yielding a 25-kDa fragment, while preserving the microtubule binding repeat domain (13). PubMed:24027553
Evidence supporting a role for thrombin in tau proteolysis came initially from an in vitro study showing that thrombin degraded recombinant full-length tau from the N-terminus yielding a 25-kDa fragment, while preserving the microtubule binding repeat domain (13). PubMed:24027553
A later study, however, showed that in N2a neuroblastoma cells expressing a construct of only the tau repeat domain, thrombin cleavage could still occur, indicating additional cleavage sites (15). Similar results were observed in an in vitro assay (15). PubMed:24027553
Thrombin signaling can also activate caspases (36). Proteasomal impairment appears to be upstream of caspase activation, as inhibiting the proteasome with epoxomicin (EPX) led to activation of caspase-3 in primary neurons (63) and in a neuroblastoma cell line expressing wild-type tau (64). PubMed:24027553
These RBC microparticles can initiate and propogate thrombin generation (Rubin et al, 2013). PubMed:25307023
However, 6 years later, Heyes and co-workers demonstrated in an experimental study in rats that infusions of thrombin induce DIC accompanied with hemolysis and schistocytosis [89]. PubMed:29956069
However, 6 years later, Heyes and co-workers demonstrated in an experimental study in rats that infusions of thrombin induce DIC accompanied with hemolysis and schistocytosis [89]. PubMed:29956069
However, 6 years later, Heyes and co-workers demonstrated in an experimental study in rats that infusions of thrombin induce DIC accompanied with hemolysis and schistocytosis [89]. PubMed:29956069
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