Fibrinogen and/or Fibrin as a Cause of Neuroinflammation Volume 5 - Issue 4

Nurul Sulimai¹ and David Lominadze²*

• ¹Department of Surgery, University of South Florida Morsani College of Medicine, USA
• ²Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, USA

Received:April 6, 2021   Published:April 14, 2021

Corresponding author: David Lominadze, Department of Surgery, USF Health-Morsani College of Medicine, USA

DOI: 10.32474/OJNBD.2021.05.000217

Abstract PDF

Involvement of fibrinogen(Fg) and fibrin during various pathologies associated with neuroinflammatory diseases associated with memory reduction are well known. Elevated level of Fg, called hyperfibrinogenemia (HFg) (e.g. ≥ 4±0.1 mg/ml of plasma during inflammation vs.~2±0.1 mg/ml of normal plasma [1]), accompanies inflammatory diseases such as stroke [2,3], hypertension [1,4], diabetes [5] and traumatic brain injury (TBI) [6-9]. Blood level of Fg increases during inflammation in general [10]. HFg is considered not only a marker of inflammation [11] but also a cause of inflammatory responses [12-16]. Gradual extravascular deposition of Fg in the brain accelerates neurovascular damage and promotes neuroinflammation [17,18]. It has been shown that Fg is associated with an increased risk of dementia and AD [19]. Derivative of Fg, fibrin have been found postmortem in the brains of patients with TBI [18,20,8], Alzheimer’s Disease (AD) [21], and multiple sclerosis (MS) [22]. Elevated blood levels of Fg (HFg) are found to be associated with increased risk of AD, cognitive decline, and dementia [19,23]. Furthermore, formations of plaques containing Fg/fibrin were found in inflammatory neurodegenerative diseases associated with memory reduction such as AD [24], MS [25], and TBI [26]. Strong association of Fg/fibrin with amyloid beta (Aβ) peptide was linked to severity of AD [24].
In fact, it has been shown that Aβ mediates formation of clots with abnormal structure and resistance to fibrinolysis [27]. This can be a possible mechanism for Fg-Aβ complex and subsequent plaque formation that is highly resistant to degradation. Although Fg/fibrin [28] and Aβ [29,30] containing plaque formations are the hallmark of AD [28,31,24], some studies indicate that content of Aβ has limited effect on memory [32,33]. These results suggest that formation of Fg-Aβ complex can have a greater effect on loss of memory than deposition of Fg or Aβ alone. Thus, although Aβ is known to be associated with AD [24], a greater role of cellular prion protein (PrPC) in memory reduction has been shown [32,33]. There are data indicating that PrPC is involved in TBI-associated memory reduction [34]. We have recently shown that Fg can specifically associate with its receptor PrPC on the surface of astrocyte [35,36] and others have found that Fg interacts with non-digestive PrP^Sc [37]. Our data showed that Fg can form a complex with PrPC in extravascular space during mild-to-moderate TBI [9]. As for the functional effects, it has been indicated that Fg that escaped from ruptured brain vessels causes astrocyte scar formation [38] and axonal damage [39]. Our data showed that Fg, which was transcytosed through endothelial cells (ECs) of non-damaged cerebral microvessels deposited in vasculo-astrocyte interfaces [40]. We found that Fg can activate astrocytes [40,41,35]. Furthermore, these effects of extravasated Fg were associated with neurodegeneration [40] and memory reduction during TBI [9,40,42].
All these data indicate an undoubtful role of Fg in inflammatory neurodegenerative diseases associated with memory impairment. However, blood-clotting proteins generate thrombin, which catalyzes the conversion of Fg (factor I) - a soluble plasma protein - into long, sticky threads of insoluble fibrin (factor Ia). Thrombin is a serine protease that is generated by proteolytic cleavage of its inactive precursor, prothrombin. Neurons and glial cells can release prothrombin and thrombin [43]. Therefore, extravasated Fg that is immobilized in extravascular space, eventually, will be converted to fibrin. In literature, the terms Fg and fibrin are often used interchangeably that creates a confusion: it becomes unclear if effects are caused by soluble Fg or its hardened, insoluble derivative – fibrin (a monomer). It has been shown that Fg does not cross blood brain barrier (BBB) in the normal brain of young mice [44]. However, our data showed that at higher (4 mg/ml) than physiological blood level, Fg not only increases EC layer permeability to albumin but itself moves through the endothelium [13]. Furthermore, we found that cerebrovascular permeability was increased in acute conditions of a HFg [12]. Similarly, cerebrovascular permeability was increased in transgenic mice exhibiting inherent HFg [45]. Using our dualtracer probing method, we found that HFg-induced cerebrovascular protein crossing occurred mainly via transcellular pathway [46,45]. Effects of HFg on formation of caveolae and caveolar transcytosis in vitro [47], and an increased cerebrovascular permeability mainly via caveolar transcytosis have been shown [45,48,46]. All these data indicate that, most likely, blood soluble protein - Fg and not its insoluble derivative fibrin, crosses walls of small cerebral vessels during various neuroinflammatory pathologies accompanied with HFg. Crossing the walls of unruptured cerebral microvessels for fibrin that is characterized with high aggregative properties and lesser flexibility is very unlikely.
While in the extravascular space, Fg interacts with its receptors intercellular adhesion molecule 1 (ICAM-1) and PrPC [49-51] on the surface of astrocytes [35]. It is possible that Fg can reach neurons and on their surface interact with its receptors - ICAM-1 and PrPC. Thus, these interactions will most likely lead to formation of Fg-PrPC complexes. As Fg is immobilized in extravascular space, it becomes an easy target for thrombin that is released from neurons and glial cells [43]. The rate of plasma Fg (0.1 mg/ml) polymerization is about 23±2 x10-5sec-1, while release of fibrinopeptides A and B from it via enzymatic (thrombin-catalyzed cleavage) step may take from 40 to 120 min [52], maybe even faster. As a consequence of Fg’s conversion to fibrin in Fg-PrPC complex, a highly resistant to enzymatic degradation, fibrin-PrPC complex will be formed. All further effects, including possible formation plaques, would be a result of specific properties of fibrin deposited in the brain extravascular space. Therefore, in our opinion, we need to be careful in describing effects of Fg, when in blood, crosses the vascular wall, deposits in extravascular space and forms complexes with other proteins, and fibrin (which can be formed in blood but least likely to extravasate) that is formed in extravascular space and by creating undegradable protein complexes (and possibly plaques) leads to memory reduction.

Keywords: Memory impairment; Neurodegeneration

This work was supported in part by funding from the National Institutes of Health - HL-146832.

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