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.

ALS mice improved with stem cell therapy; first step for science in finding better treatment  

TAMPA, Fla. (May 12, 2017) – Researchers at the University of South Florida show in a new study that bone marrow stem cell transplants helped improve motor functions and nervous system conditions in mice with the disease amyotrophic lateral sclerosis (ALS) by repairing damage to the  blood-spinal cord barrier.

In a study recently published in the journal Scientific Reports, researchers in USF’s Center of Excellence for Aging and Brain Repair say the results of their experiment are an early step in pursuing stem cells for potential repair of the blood-spinal cord barrier, which has been identified as key in the development of ALS. USF Health Professor Svitlana Garbuzova-Davis, PhD, led the project.

Previous studies in development of various therapeutic approaches for ALS typically used pre-symptomatic mice. This is the first study advancing barrier repair that treats symptomatic mice, which more closely mirrors conditions for human patients, Dr. Garbuzova-Davis said.

Svitlana Garbuzova-Davis, PhD, led the study.

Using stem cells harvested from human bone marrow, researchers transplanted cells into mice modeling ALS and already showing disease symptoms. The transplanted stem cells differentiated and attached to vascular walls of many capillaries, beginning the process of blood-spinal cord barrier repair.

The stem cell treatment delayed the progression of the disease and led to improved motor function in the mice, as well as increased motor neuron cell survival, the study reported.

ALS is a progressive neurodegenerative disease that affects neuronal cells in the brain and the spinal cord, which send signals to control muscles throughout the body. The progressive degeneration of motor neuron cells leads to death from ALS. More than 6,000 Americans each year are diagnosed with the disease.

Because stem cells have the ability to develop into many different cell types in the body, researchers at USF’s Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair have focused on using stem cells to restore function lost through neurodegenerative disorders or injuries.

Damage to the barrier between the blood circulatory system and the central nervous system has been recently recognized as a factor in ALS development, leading researchers to work on targeting the barrier for repair as a potential strategy for ALS therapy.

In this study, the ALS mice were given intravenous treatments of one of three different doses of the bone marrow stem cells. Four weeks after treatment, the scientists determined improved motor function and enhanced motor neuron survival. The mice receiving the higher doses of stem cells fared better in the study, the researcher noted.

The transplanted stem cells had differentiated into endothelial cells – which form the inner lining of a blood vessel, providing a barrier between blood and spinal cord tissue – and attached to capillaries in the spinal cord. Furthermore, the researchers observed reductions in activated glial cells, which contribute to inflammatory processes in ALS.

USF Health Morsani College of Medicine researchers Crupa Kurien, Avery Thomson, Dimitri Falco, Sohaib Ahmad, Joseph Staffetti, George Steiner, Sophia Abraham, Greeshma James, Ajay Mahendrasah, Paul R. Sanberg and Cesario V. Borlongan joined in the project. The study was funded by the National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Read the full study here.

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USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, the Biomedical Sciences Graduate and Postdoctoral Programs, and the USF Physicians Group. The University of South Florida, established in 1956 and located in Tampa, is a high-impact, global research university dedicated to student success. USF is ranked in the Top 30 nationally for research expenditures among public universities, according to the National Science Foundation. For more information, visit www.health.usf.edu

News release by Vickie Chachere, USF Research and Innovation

Media contact: 
Anne DeLotto Baier, USF Health Communications
abaier@health.usf.edu or (813) 974-3303