The complement system controls the blood-brain barrier in the aging brain
German-American research team has demonstrated a novel role of the complement system in brain aging process
As people get older, structures and functions in the brain change. An important age-related change is the increased permeability of the blood-brain barrier, which physiologically allows the transfer of a limited number of substances from the bloodstream into the brain and vice versa. Among other things, this can promote the development of neurodegenerative diseases such as Alzheimer's dementia. A number of previous studies suggest that the reduced function of the blood-brain barrier is related to immunologically induced inflammatory processes - but the exact mechanisms behind this are still poorly understood. Jörg Köhl, member of the board of the Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI) and director of the Institute of Systemic Inflammation Research (ISEF), University of Lübeck (UzL) and University Medical Center Schleswig-Holstein (UKSH), Campus Lübeck together with the research group of Hui Zheng (Huffington Center on Aging, Houston, USA) identified a mechanism by which the complement system regulates vascular inflammation and the associated disturbed function of the blood-brain barrier during the aging process. The researchers recently published their results in the Journal of Clinical Investigation.
The complement system is part of the innate immune defense. It consists of more than 40 proteins that occur in the blood and as receptors on the surface of cells. These proteins include the so-called complement factors and their cleavage products, as well as receptors that recognize these cleavage products. The system plays an important role in the defense against microorganisms. It signals the presence of pathogens and the binding of antibodies to pathogens, but also to the body's own structures. However, due to the dysregulation of the complement system, an excessive inflammatory reaction can also occur in the course of certain diseases, causing tissue damage. While most complement proteins are produced in the liver, it has long been known that both complement factors and complement receptors are also produced directly in the brain. Of particular importance is complement factor C3, which can be split into two parts, C3b and C3a. C3a triggers its biological effect by binding to the C3a receptor, which is present on vascular endothelial cells, i.e. the cells that line the inside of blood vessels, and various brain cells.
In the now published study, the researchers were able to show that C3/C3a production increases in the aging brain and that activation of the C3a receptor on vascular endothelial cells of the brain occurs. In response to this, these cells produce an increased amount of a certain adhesion molecule, which leads to an increased immigration of lymphocytes, i.e. special immune cells, into the brain. In addition, the activation of the C3a receptor on the vascular endothelial cells induces the release of intracellular calcium ions. This leads to a disruption of a special protein on the vascular endothelial cells, which is of central importance for the connection of these cells. A disruption of these connections results in an increased permeability of the blood-brain barrier. As a result, the brain is no longer so well separated from the rest of the body, so that inflammations from the environment can more easily spread to the brain.
To elucidate this disease mechanism, the researchers developed a transgenic mouse strain in which the mice are genetically modified so that they no longer form a C3a receptor on the vascular endothelial cells. The specific elimination of the C3a receptor in the vascular endothelial cells not only protected the mice from increased permeability of the blood-brain barrier in old age. It also reduced the inflammatory activity of special immune cells in the brain, the microglia cells, and increased the volume of the hippocampus and cerebral cortex of aging mice compared to animals with C3a receptor. The hippocampus is of particular importance for learning and memory processes.
"Our findings indicate a new regulation of the blood-brain barrier controlled by the complement system and thus the activation of immune cells, inflammation and degeneration in the aging brain," said Köhl. "The data suggest that the targeted blocking of individual elements of the complement system could lead to a significant improvement in vascular function and a reduction in the permeability of the blood-brain barrier, thus leading to a reduction in the number of blood cells in the aging brain.
Propson N.E., Roy E.R. Litvinchuk A., Köhl J., Zheng H. Endothelial C3a receptor mediates vascular inflammation and BBB permeability during aging. 2020; first published Sep 29, 2020.
In the aging brain, C3/C3a production increases and the C3a receptors on vascular endothelial cells of the brain are activated. In response, these cells produce increased amounts of the adhesion molecule VCAM-1, which leads to an increased migration of lymphocytes into the brain. In addition, the activation of the C3a receptor leads to a mobilization of calcium ions in the cells, resulting in a disruption of the vascular endothelial cadherin, which is of central importance for the interconnection of these cells. Breaking these connections results in increased permeability of the blood-brain barrier.