A University of Florida researcher is among a team of scientists who have discovered a protein’s role in controlling the brain’s inflammatory response to injury and disease. The finding may hold significance for the treatment of Alzheimer’s disease, multiple sclerosis and AIDS-related dementia — all conditions marked by brain degeneration associated with chronic inflammation.
“It has long been suspected that the body’s usual full-fledged reaction to injury — pain, swelling, redness and heat — are dulled in the central nervous system in order to prevent damage to the brain, which can’t be regenerated,” said Wolfgang “Jake” Streit, a professor in the UF College of Medicine department of neuroscience.
“But for the first time, we have pinpointed a specific molecule — a protein called OX2 — that causes this inhibition and keeps the inflammatory processes of the brain in check. In laboratory animal experiments, when OX2 was absent, the inflammation was out of control. This finding is very important for understanding brain diseases such as Alzheimer’s, in which inflammation plays a role,” he said.
OX2 is an immunological protein found in lymph organs throughout the body and also is prevalent in the brain. When OX2 was absent in mice, Streit and his colleagues found that specialized damage-fighting cells in the central nervous system, called microglial cells, became excessively active. The finding suggests that OX2 controls microglia and thereby represses inflammation in the brain, Streit said.
Microglia in the central nervous system normally function like less-active cousins of white blood cells, which aggressively battle damage in the rest of the body. But when injury or disease affect nerve cells, the microglia become active, causing inflammation in the brain. Usually, this microglial activation is temporary, and the cells return to normal relatively quickly.
But in disorders thought to be associated with chronic brain inflammation, microglia remain highly active for long periods, even decades in Alzheimer’s disease, Streit said. These findings suggest that people with brain inflammatory diseases may have insufficient levels or activity of the OX2 protein and therefore diminished control over the inflammatory response, he said.
Alzheimer’s disease is an irreversible, progressive brain disorder that results in memory loss, behavior and personality changes, and a decline in thinking abilities. According to the National Institutes of Health, as many as 4 million people now have the disease, and 360,000 new cases are expected to develop each year — a number projected to increase as the population ages. Although the risk of developing the disease increases with age, Alzheimer’s and dementia symptoms are not part of normal aging. They are caused by disorders that affect the brain. In the absence of disease, the human brain often can function well into the 10th decade of life, according to the NIH.
With normal aging, microglial activation increases in the brain. The process is exacerbated and accelerated in those with Alzheimer’s, so that a 50- or 60-year-old with Alzheimer’s would show microglial changes similar to those in the brain of a normal 90-year-old, Streit said.
The cause of this is unknown. “But the better we understand mechanisms that regulate microglial activation, the greater chance we’ll have of someday being able to enhance or stimulate these inhibitory effects in order to prevent this chronic inflammation of the brain and help prevent diseases like Alzheimer’s,” he said. “The obvious next step in the research process is to look for levels of OX2 in people with Alzheimer’s disease or other brain inflammatory conditions such as multiple sclerosis,” Streit said.
For the animal experiments reported in Science, Streit induced a nerve injury in 36 mice; half had normal levels of OX2 and half were OX2-deficient. By cutting a peripheral nerve close to the surface of the skin behind the ears of the mice, he injured nerve cells in the brain stem, causing the microglial cells to go to work.
In the OX2-deficient mice, microglial response was accelerated dramatically, showing a detectable activation two days after the procedure and maximal activation reached by the fourth day. In contrast, microglia in normal mice became active four days after the procedure, with peak activation seven days afterward.
The DNAX researchers found similar results in a separate experiment in which they induced inflammation in the brains of mice, replicating some of the characteristics of multiple sclerosis, such as tissue damage and neurological defects. Onset of the brain inflammation in the OX2-deficient mice was advanced by two to four days, which the researchers considered “a major change” in the usually short 10- to 12-day time frame of the inflammation being triggered. Streit and other UF researchers are continuing to investigate the molecular mechanisms of brain inflammation and its effect on regeneration in the central nervous system, which may also shed light on other conditions, such spinal cord injury and traumatic brain injury.
Streit conducted the research in collaboration with scientists at the DNAX Research Institute of Molecular and Cellular Biology in Palo Alto, Calif. The institute is affiliated with the pharmaceutical company Schering-Plough Corp. The results are reported in the Dec. 1 issue of the journal Science.