Cholesterol Buildup Limits Regeneration of Nerve-cell-protecting Sheath, Study Shows
The nerve-cell-protecting myelin sheath’s failure to remove cholesterol after the membrane has been damaged limits its ability to regenerate, German researchers report.
Their finding has important implications for multiple sclerosis because a hallmark of the disease is nerve cell deterioration stemming from damaged myelin. Cholesterol is a waxy, fatty substance found in all cells whose buildup in blood increases the risk of a heart attack.
Myelin membrane cells’ failure to remove cholesterol increases with age, according to the mouse study that the Germans did.
Their findings may explain why the injuries that multiple sclerosis causes are so difficult to heal.
The team titled their research, which appeared in the journal Science, “Defective cholesterol clearance limits remyelination in the aged central nervous system.”
Cholesterol, a main component of myelin, accumulates in cells that should be removing it. This buildup triggers an inflammatory reaction that may further prevent healing.
“When myelin is destroyed, the cholesterol released has to be removed from the tissue,” he added. But the cells that remove myelin debris can’t process cholesterol.
These immune cells, known as microglia and macrophages, remove myelin debris by digesting it. Since they can’t process cholesterol, they leave this task to molecules whose responsibility is transporting it out of myelin cells.
Myelin cells can get jammed with cholesterol, however. At that point, it starts forming needle-shaped crystals that can damage the cell. This triggers an inflammatory reaction, in which microglia and macrophages release substances that attract more immune cells to the site.
“Very similar problems occur in arteriosclerosis,” or hardening of the arteries, Simons said.
Researchers learned that as mice age, their microglia and macrophages become less effective at clearing myelin debris.
Their findings were not all bad news, however. They discovered that a compound that helps transport cholesterol out of myelin cells can boost myelin repair.
“When we treated the animals with a medication that facilitates the transport of cholesterol out of the cells, inflammation decreased and myelin was regenerated,” Simons said.
The team identified a specific type of myelin-generating cell in another study. Titled “BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions,” it appeared in the journal Science Translational Medicine.
This research gave scientists better insight into how and when the body forms myelin. This information will be crucial to researchers’ attempts to develop regenerative medications.
Working with Christine Stadelmann, a professor at the University of Göttingen, Simons discovered what cells called oligodendrocytes look like when they are producing myelin. The team called the cells BCAS1-positive oligodendrocytes.
Earlier, scientists were able to distinguish only between oligodendrocyte precursor cells and mature oligodendrocytes, not those that were in the midst of generating myelin.
“We believe that the BCAS1-positive oligodendrocytes that we discovered represent an intermediate stage in the development of myelin-forming cells,” Simons said. “In humans they can only be identified for a relatively short period of time, exactly then when myelin is actually being formed.”
The cells are found in newborns, who produce myelin at a high rate. In adults, the cells are lost. But they can reform when myelin regeneration is necessary.
“We hope that the BCAS1-positive cells will help us to identify new regenerative medicines,” Simons said.
The team plans to continue exploring ways of promoting remyelination. One focus will be seeing whether transporting cholesterol out of brain cells could be a way to treat multiple sclerosis.