Hyperfibrinogenemia-mediated astrocyte activation

Abstract

Fibrinogen (Fg)-containing plaques are associated with memory loss during various inflammatory neurodegenerative diseases such as Alzheimer’s disease, multiple sclerosis, stroke, and traumatic brain injury. However, mechanisms of its action in neurovascular unit are not clear. As Fg is a high molecular weight blood protein and cannot translocate far from the vessel after extravasation, we hypothesized that it may interact with astrocytes first causing their activation. Cultured mouse cortical astrocytes were treated with Fg in the presence or absence of function-blocking anti-mouse ICAM-1 antibody, or with medium alone (control). Expressions of intercellular adhesion molecules 1 (ICAM-1) and tyrosine receptor kinase B (TrkB) as markers of astrocyte activation, and phosphorylation of TrkB (pTrkB) were assessed. Fg dose-dependently increased activation of astrocytes defined by their shape change, retraction of processes, and enhanced expressions ICAM-1 and TrkB, and increased pTrkB. Blocking of ICAM-1 function ameliorated these Fg effects. Data suggest that Fg interacts with astrocytes causing overexpression of ICAM-1 and TrkB, and TrkB phosphorylation, and thus, astrocyte activation. Since TrkB is known to be involved in neurodegeneration, interaction of Fg with astrocytes and the resultant activation of TrkB can be a possible mechanism involved in memory reduction, which were observed in previous studies and were associated with formation of complexes of Fg deposited in extravascular space with proteins such as Amyloid beta or prion, the proteins involved in development of dementia.

Fibrinogen Interaction with Astrocyte ICAM-1 and PrPC Results in the Generation of ROS and Neuronal Death

“…The data showed that Fg was co-localized and thus strongly associated with astrocyte ICAM-1 and PrP C , suggesting that it is possibly binding to these receptors on the surface of astrocytes. This is the first time a Fg specific interaction with astrocytes was visualized, confirming our previous finding that Fg could be associated with ICAM-1 [ 21 ] and PrP C with high specificity [ 16 , 36 , 39 ]. Thus, the increased respective PLA signals can be the result of a Fg interaction with over-expressed astrocyte ICAM-1 and PrP C .…”

“…We used this method to observe interactions between Fg and its receptors ICAM-1 and PrP C on the surface of astrocytes. In a preliminary study, the use of a higher content of Fg (2 or 4 mg/mL), similar to those used in our previous studies [ 16 , 21 ], resulted in signal saturation. Therefore, we used lower doses of Fg to detect if there was an association of Fg with its astrocyte receptors.…”

“…Therefore, we used lower doses of Fg to detect if there was an association of Fg with its astrocyte receptors. We have previously showed that astrocytes express ICAM-1 [ 21 ]. To specifically validate these results, we tested the expression of ICAM-1 in astrocytes in response to an interaction with Fg.…”

“…Clinically, Fg immunoreactivity can be found in postmortem brain sections taken from patients anywhere from hours up to as long as 18 years after a fall [ 35 ]. Pro-Inflammatory effects of excess Fg, such as vasoconstriction, vascular permeability, and astrocyte, neuronal and glial activation, are well documented [ 18 , 21 , 22 , 36 ]. We have shown previously that deposition of extravasated Fg between a vessel and astrocyte endfeet in the animal model of TBI coincides with increased neurodegeneration and a reduction in STM [ 5 ].…”

“…We have previously shown that Fg interacts with ICAM-1 on endothelial cell surfaces causing vasoconstriction [ 18 ] and an increase in vascular permeability [ 19 , 20 ]. We have also shown that elevated levels of Fg, called hyperfibrinogenemia (HFg), causes astrocyte activation in vitro [ 21 ]. Whereas in an in vivo study, using the cortical contusion injury model of mild-to-moderate TBI, the deposition of Fg in the extravascular space resulted in a significant change of astrocyte morphology, indicating their activation that coincided with increase in neuronal degeneration [ 5 ].…”