USF Health preclinical discovery may help identify new therapeutic targets for Alzheimer’s disease, traumatic brain injury and other neurodegenerative diseases

TAMPA, Fla (Nov. 5, 2021) — Neuroinflammatory diseases, including Alzheimer’s disease and traumatic brain injury, have been linked to deposits of a tough protein known as fibrin, derived from the blood clotting factor fibrinogen. These mesh-like fibrin deposits occur outside blood vessels in the brain, contributing to the death of certain central nervous system cells (neurons) that eventually leads to impaired memory.

Now for the first time, a team at the University of South Florida Health (USF Health) Morsani College of Medicine, reported that before soluble fibrinogen is converted into insoluble fibrin molecules that can adversely accumulate, it can connect directly with neurons and cause a damaging inflammatory reaction. The researchers further discovered that fibrinogen specifically binds to two fibrinogen receptors on the surface of neurons: cellular prion protein (PrP^C) and intracellular adhesion molecule-1 (ICAM-1).

USF Health’s David Lominadze, PhD, a professor of surgery and molecular pharmacology and physiology, investigates how microvascular changes induced by neuroinflammation may damage cognition, including short-term memory. | Photo by Allison Long, USF Health Communications.

Their preclinical study was published Sept. 18 in a special issue of MDPI–Biomolecules entitled “Prions and Prion-Like Mechanisms in Disease and Biological Function.”

The findings have implications for identifying targeted therapies to help prevent or stop 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 overlooked culprits involved in the processes of neurodegeneration and resulting memory loss,” said principal investigator David Lominadze, PhD, a USF Health professor of surgery, and molecular pharmacology and physiology. “Our study shows that fibrinogen is not only a marker (biological indicator) of inflammation but can be a cause of inflammation in the brain.”

Fibrinogen is a blood plasma protein naturally produced in the liver and travels throughout the bloodstream to other organs and tissues. Outside of blood vessels, fibrinogen is converted by the enzyme thrombin into fibrin during blood clot formation, playing a key role in wound healing.

Dr. Lominadze’s laboratory focuses on understanding molecular changes affecting circulation of blood in the body’s smallest blood vessels — including how microvascular changes induced by inflammation may damage cognition, in particular short-term memory.

Dr. David Lominadze (sitting) with postdoctoral research scholar Nurul Sulimai, PhD (left), and senior biological scientist Jason Brown | Photo by Allison Long, USF Health Communications.

Dr. Lominadze and others have shown that inflammatory disease is associated with a higher concentration of fibrinogen in the blood, increased generation of potentially damaging free radicals, neuronal cell activation and microvascular permeability. In previous studies using their mouse model for mild-to-moderate traumatic brain injury, Dr. Lominadze’s group reported that fibrinogen after crossing the vascular wall accumulated in spaces between the microvessels and astrocytes (another brain cell type connecting vessels and neurons) and activated the astrocytes. This activation coincided with increased neurodegeneration and reduced short-term memory.

In this latest study, the USF Health researchers tested whether fibrinogen, beside interacting with astrocytes, could connect directly with neurons — nerve cells critical for carrying information throughout the human body and coordinating all necessary functions of life.

They treated healthy mouse brain neurons grown in a petri dish with fibrinogen. Fibrinogen increased the death of these neurons, a process that was not influenced by the presence or absence of a thrombin inhibitor preventing the conversion of fibrinogen to fibrin. The finding suggests that soluble fibrinogen and, at later stages, fibrin can have similar toxic effects on neurons.

Furthermore, blocking the function of PrP^C and ICAM-1 fibrinogen receptors on the surface of neurons (essentially stopping fibrinogen from binding tightly to these receptors) reduced inflammatory reactions resulting in neurodegeneration.

“The study revealed that an interaction between fibrinogen and neurons induced an increase in the expression of proinflammatory cytokine interleukin-6, enhanced oxidative damage, and neuronal death, in part due to its direct association (contact) with neuronal PrP^C and ICAM-1,” the study authors wrote.

Interactions of blood plasma protein fibrinogen with its receptors, cellular prion protein (above) and intercellular adhesion molecule (below), on the surface of neurons are shown with red dots using a method called proximity ligation assay.  The presence of red dots indicates interaction of the target protein with its receptor. Neuronal nuclei are shown in blue.  — Microscopic images courtesy of Lominadze Laboratory, USF Health

More research is needed. But altogether the USF Health study suggests that short-term memory problems stemming from neurodegenerative diseases with underlying inflammation may be alleviated by several interventions, Dr. Lominadze said. These include “dampening general inflammation, decreasing fibrinogen concentration in the blood by reducing the synthesis of fibrinogen, and blocking the binding of fibrinogen to its neuron receptors,” he said.

The USF Health research was supported by a grant from the National Heart, Lung and Blood Institute, part of the National Institutes of Health.

A leading expert on the role of monocytes and macrophages (types of immune cells) in atherosclerosis and other chronic inflammatory conditions delivered the keynote address Nov. 7 at the USF Health Heart Institute’s 2^nd Annual Scientific Colloquium.

Gwendalyn Randolph, PhD, an immunologist by training, began her career by studying how innate immune cells travel around the body and along the way began discovering connections between cardiovascular disease, lipid metabolism and the gut.

USF Health Heart Institute Director Samuel Wickline, MD, with speakers at the Institute’s 2nd Annual Scientific Symposium. From left: David Lominadze, PhD, USF Health professor of surgery; Gwendalyn Randolph, PhD, Unanue Distinguished Professor of Pathology and Immunology at Washington University School of Medicine in St. Louis; Dr. Wickline; and Travis Jackson, PhD, USF Health associate professor of molecular pharmacology and physiology.

For the Heart Institute talk, Dr. Randolph, the Emil R. Unanue Distinguished Professor of Pathology and Immunology at Washington University School of Medicine in St. Louis, focused on research investigating what drives inflammation in atherosclerosis – the most common cause of heart attacks.  She shared her work on the trafficking of immune cells and the lipoproteins that carry cholesterol through the bloodstream to deposit inside the artery walls.

“Dr. Randolph’s work in the field of atherosclerosis has produced novel and important insights into the critical cell types that are responsible for forming atherosclerotic plaques in patients with heart disease,” said Samuel Wickline, MD, professor of cardiology and director of the USF Health Heart Institute. “She also has elucidated the molecular factors that attract these cells to plaques and cause them to grow and become unstable, which leads the plaques to break down and clot. This process can ultimately result in blockage of vessels that supply blood to the heart and brain, causing heart attacks and strokes.”

Research by Dr. Randolph, this year’s keynote speaker at the colloquium, has yielded new insights into how immune cells drive inflammation contributing to atherosclerotic plaques in heart disease.

Mouse model studies by Dr. Randolph and others have shown white blood cells, known as monocytes, contribute to the initial build-up of atherosclerotic plaques.

The cascade of events leading to atherosclerosis can take decades.  Initial damage to the inner wall (endothelium) of arteries under the influence of high cholesterol levels triggers a molecular signal that attracts monocytes to travel from the bloodstream into developing plaques. These recruited monocytes are converted into macrophages that take up (eat) the cholesterol trapped in blood vessels and eventually die off. But before that happens, they stay busy secreting molecules that drive plaque inflammation  and weaken the vessel wall, leading to plaque rupture, clotting, and coronary artery obstruction.

In terms of developing new therapies to halt or reverse atherosclerosis, Dr. Randolph said, her research suggests that upstream targeting of recruited monocytes — either before or just after these immune cells arrive in plaques — may be more beneficial than targeting the fat-laden macrophages known as foam cells. Experiments with fluorescent tracers indicate that monitoring endothelial cells lining the arterial wall may be a way to track monocyte migration, she added.

Thomas McDonald, MD, a professor in the USF Health Morsani College of Medicine’s Department of  Molecular Pharmacology and Physiology and member of the Heart Institute, listens to Dr. Randolph’s talk.

In addition to Dr. Randolph, two new faculty members recruited this summer to the USF Health Heart Institute – Travis Jackson, PhD, and David Lominadze, PhD — provided overviews of their National Institutes of Health-funded research.

Dr. Jackson, an associate professor in the Department of Molecular Pharmacology and Physiology, discussed his translational work in therapeutic hypothermia — investigating ways to optimize cold-shock proteins and cold-stress hormones to increase the benefits of cerebroprotective cooling for traumatic brain injury. Dr. Lominadze, a professor in the Department of Surgery, presented research looking into the interactions of blood cells and the endothelium, with the aim of better understanding the microcirculatory disorders associated with cardiovascular and cerebrovascular diseases.

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The USF Health Heart Institute is scheduled to move to the new USF Health Morsani College of Medicine building in Water Street Tampa in late February 2020.  Its annual scientific colloquium will be held in the new home next year, and continue to evolve with the growth of the Institute, Dr. Wickline said.

“We will expand the program to cover other topics of interest to the cardiovascular community such as genetic heart diseases, heart failure, peripheral vascular disease, and gene therapy.”

-Photos by Allison Long, USF Health Communications and Marketing