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Molecular Sensor May Detect MS Prior to Symptoms

12/18/2013

Scientists at the Gladstone Institutes have devised a new molecular sensor that may one day be used to detect MS at its earliest stages—even before the onset of physical signs.

In a new study from the laboratory of Gladstone investigator Katerina Akassoglou, Ph.D., scientists reveal in animal models that the heightened activity of a protein called thrombin in the brain could serve as an early indicator of MS. By developing a fluorescently labeled probe specifically designed to track thrombin, the team found that active thrombin could be detected at the earliest phases of MS—and that this active thrombin correlates with disease severity.

These findings, reported online in Annals of Neurology, shed light on some of MS’ most elusive mechanisms and could spur the development of a much-needed early-detection method for this devastating disease, according to researchers.

Last year, Akassoglou and her team found that a key step in the progression of MS is the disruption of the blood brain barrier (BBB). This barrier physically separates the brain from the blood circulation and if it breaks down, a blood protein called fibrinogen seeps into the brain. When this happens, thrombin responds by converting fibrinogen into fibrin—a protein that should normally not be present in the brain. As fibrin builds up in the brain, it triggers an immune response that leads to the degradation of the nerve cells’ myelin sheath, over time contributing to the progression of MS.

“We already knew that the buildup of fibrin appears early in the development of MS—both in animal models and in human patients, so we wondered whether thrombin activity could in turn serve as an early marker of disease.” said Dr. Akassoglou, who directs the Gladstone Center for In Vivo Imaging Research (CIVIR). “In fact, we were able to detect thrombin activity even in our animal models even before they exhibited any of the disease’s neurological signs.”

In laboratory experiments on mice modified to mimic the signs of MS, the team employed an Activatable Cell-Penetrating Peptide (ACPP), a special type of molecular probe that delivers fluorescent agents to a region of interest. For this study, they developed a thrombin-specific probe that could track thrombin activity in mice as the disease progressed. They then carefully analyzed where—and at what stage of disease—thrombin activity was found.

“We detected heightened thrombin activity at specific disease ‘hot-spots,’ regions where neuronal damage developed over time,” said GladstoneStaff Research Scientist Dimitrios Davalos, Ph.D., associate director of the CIVIR and one of the paper’s lead authors. “And when we compared these results to those of a separate, healthy control group of mice, we saw that thrombin activity in the control group was wholly absent.”

The team’s results offered significant support for the notion that thrombin activity is directly tied to the degradation of nerve cell’s myelin sheath—and the subsequent destruction of nerve cells—that characterizes MS. They also shed light on what has been a long-standing mystery: the underlying molecular processes that kick-start the progression of MS.

“In the future,” said Dr. Akassoglou, “this thrombin-specific probe could be developed to one day allow for early patient diagnosis and therapeutic intervention—including a way to effectively monitor how patients are responding to the latest treatments.”

 



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