Neuroinflammatory diseases, including Alzheimer's disease and traumatic brain injury, are associated with the deposition of tough proteins called fibrin, which are derived from the coagulation factor fibrinogen. These reticular fibrin deposits occur outside cerebral blood vessels, leading to the death of some central nervous system cells (neurons) and eventually memory impairment.
Now, for the first time, a team from the morsani School of medicine at the University of South Florida Health Center (USF Health) has reported that soluble fibrinogen can directly connect with neurons and cause a destructive inflammatory response before it is converted into insoluble fibrin molecules. The researchers further found that fibrinogen specifically binds to two fibrinogen receptors on the surface of neurons: cellular prion protein (PrPC) and intracellular adhesion molecule-1 (ICAM-1).
Their preclinical study, entitled "prions and prion like mechanisms in disease and biological function", was published in the special issue of biomolecules.
The study was published in the special issue of biomolecules (latest influencing factor: 4.879) on September 18, 2021
This finding has implications for identifying targeted therapies that can help prevent or prevent neurodegeneration in Alzheimer's disease, traumatic brain injury, or other chronic neuroinflammatory diseases associated with abnormal vascular permeability (leakage) in the brain.
"Fibrinogen is one of the neglected culprits in the process of neurodegeneration and memory loss," said lead researcher Dr. David lominadze, a professor of surgery, molecular pharmacology and physiology at USF health. "Our research shows that fibrinogen is not only a marker of inflammation (biological index), but also a possible cause of brain inflammation."
Dr David lominadze
Fibrinogen is a protein naturally produced in the liver and transmitted to other organs and tissues through the blood. Fibrinogen is outside the blood vessel and is converted into fibrin by thrombin during the formation of blood clot, which plays a key role in wound healing.
Dr lominadze's lab focuses on understanding how molecular changes that affect the blood circulation of the body's smallest blood vessels, including microvascular changes caused by inflammation, impair cognitive ability, especially short-term memory.
Studies by Dr lominadze and others have shown that inflammatory diseases are associated with increased fibrinogen concentrations in the blood, increased production of potentially damaging free radicals, neuronal cell activation and microvascular permeability. In a previous study using a mouse model to treat mild to moderate traumatic brain injury, Dr lominadze's team reported that fibrinogen accumulated and activated astrocytes in the space between microvessels and astrocytes, another type of brain cell that connects blood vessels and neurons, after passing through the blood vessel wall. This activation coincides with increased neurodegeneration and decreased short-term memory.
Dr. David lominadze (seated) and Dr. Nurul sulimai (left), a postdoctoral researcher, and Jason brown, a senior bioscientist
In this latest study, USF health researchers tested whether fibrinogen can connect directly to neurons in addition to interacting with astrocytes - which are essential for transmitting information and coordinating all necessary life functions throughout the human body.
They treated brain neurons of healthy mice grown in Petri dishes with fibrinogen. Fibrinogen increases the death of these neurons, which is not affected by the presence or absence of thrombin inhibitors that prevent the conversion of fibrinogen to fibrin. This finding suggests that soluble fibrinogen and fibrin in later stages have similar toxic effects on neurons.
In addition, blocking the function of PrPc and ICAM-1 fibrinogen receptors on the surface of neurons (basically preventing the close binding of fibrinogen to these receptors) can reduce the inflammatory response leading to neurodegeneration.
"Studies have shown that the interaction between fibrinogen and neurons leads to increased expression of proinflammatory cytokine interleukin-6 (IL-6), enhanced oxidative damage and neuronal death, in part due to its direct association (contact) with neuronal PrPc and ICAM-1," the study authors wrote.
The interaction of plasma fibrinogen with its receptors, cellular prion proteins (above) and intercellular adhesion molecules (below) on the surface of neurons is shown by red dots using a method called proximity junction assay. The presence of red dots indicates the interaction between the target protein and its receptor. The neuronal nuclei are shown in blue.
More research is needed. But overall, USF health's research suggests that short-term memory problems caused by neurodegenerative diseases caused by underlying inflammation may be alleviated by several interventions, Dr. lominadze said. These measures include "inhibiting general inflammation, reducing the concentration of fibrinogen in the blood by reducing the synthesis of fibrinogen, and preventing the binding of fibrinogen to its neuronal receptors," he said.
The USF health study was funded by the national heart, lung and Blood Institute, part of the National Institutes of Health (NIH).
