High-resolution real-time images show in mice how nerves may be damaged during the earliest stages of multiple sclerosis. The results suggest that the critical step happens when fibrinogen, a blood-clotting protein, leaks into the central nervous system and activates immune cells called microglia.
Microglia (green cells) cluster around leaking blood vessels days before neurological damage occurs in a mouse model of MS.
Credit: Courtesy of Akassoglou lab, Gladstone Institute
"We have shown that fibrinogen is the trigger," said Katerina Akassoglou, Ph.D., an associate investigator at the Gladstone Institute for Neurological Disease and professor of neurology at the University of California, San Francisco, and senior author of the paper published online in Nature Communications.
Multiple sclerosis, or MS, is thought to be an autoimmune disease in which cells that normally protect the body against infections attack nerve cells in the brain and spinal cord, often leading to problems with vision, muscle strength, balance and coordination, thinking and memory. Typically during MS, the immune cells destroy myelin, a protective sheath surrounding nerves, and eventually leading to nerve damage. The immune attack also causes leaks in the blood-brain barrier, which normally separates the brain from potentially harmful substances in the blood.
"Dr. Akassoglou has focused on the role of the blood-brain barrier leak in MS and has discovered that leakage of the blood clotting protein fibrinogen can trigger brain inflammation," said Ursula Utz, Ph.D., M.B.A., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS).
Microglia are cells traditionally thought to control immunity in the nervous system. Previous studies suggested that leakage of fibrinogen activates microglia. In this study, Dr. Akassoglou and her colleagues used a cutting-edge imaging technique called two-photon laser scanning microscopy to watch what happens in an animal model of MS.
"Our results provide the first evidence linking leakage of fibrinogen to neuronal damage," said Dr. Akassoglou, "Vascular changes are the instigator of neurotoxicity."
Using a mouse model of MS, the researchers found that leakage of fibrinogen and microglial activation occurred days before nerve damage began, suggesting they occur in an early, pre-clinical stage of the disease.
During this period, microglia changed shapes and clustered around blood vessels along with other immune cells. Further experiments suggested that fibrinogen activated microglia by binding to a receptor, called CD11b/CD18, which caused the microglia to release reactive oxygen molecules that, in turn, damaged neurons. Inhibiting the binding of fibrinogen to the receptor prevented microglial activation and nerve damage.
Current treatments for MS are designed to suppress autoimmunity. The results from this study suggest that targeting the interaction between fibrinogen and microglia may be an effective alternative. In the mice, blocking fibrinogen's blood clotting activity prevented microglial activation and nerve damage.
"Current drugs target primarily downstream events. This interaction could be an upstream target that suppresses immunity and neurodegeneration," said Dr. Akassoglou.
In 2006, Dr. Akassoglou received a Presidential Early Career Award for Scientists and Engineers, which honors and supports the finest and most promising researchers early in their careers.
This study was supported by NINDS (NS051470, NS052189, NS066361); the National Cancer Institute (CA082103); the National Center for Research Resources (RR004050), the National Heart, Lung, and Blood Institute (HL096126), the American Heart Association, the Bechtel Foundation, the Dana Program in Brain and Immuno-imaging, the H. Lundbeck A/S, the Howard Hughes Medical Institute, the National Multiple Sclerosis Society, the Nancy Davis Foundation for Multiple Sclerosis, and the March of Dimes.
Reference: Davalos et al., "Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation." Nature Communications, published online November 27, 2012. DOI: 10.1038/ncomms2230
NINDS is the nation's leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease – a burden borne by every age group, by every segment of society, by people all over the world.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
Christopher Thomas | EurekAlert!
Custom-tailored strategy against glioblastomas
26.09.2016 | Rheinische Friedrich-Wilhelms-Universität Bonn
New leukemia treatment offers hope
23.09.2016 | King Abdullah University of Science and Technology
Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of light metals.
Scientists at the University of Stuttgart have now developed two new process variants that will considerably expand the areas of application for friction stir welding.
Technologie-Lizenz-Büro (TLB) GmbH supports the University of Stuttgart in patenting and marketing its innovations.
Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of...
Optical quantum computers can revolutionize computer technology. A team of researchers led by scientists from Münster University and KIT now succeeded in putting a quantum optical experimental set-up onto a chip. In doing so, they have met one of the requirements for making it possible to use photonic circuits for optical quantum computers.
Optical quantum computers are what people are pinning their hopes on for tomorrow’s computer technology – whether for tap-proof data encryption, ultrafast...
The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.
“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...
With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.
Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...
For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.
Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...
29.09.2016 | Event News
28.09.2016 | Event News
27.09.2016 | Event News
29.09.2016 | Materials Sciences
29.09.2016 | Materials Sciences
29.09.2016 | Interdisciplinary Research