Cholesterol crystals could be the reason why the central nervous system of multiple sclerosis patients cannot regenerate, a German study has reported.
Now Professor Mikael Simons from the Technical University of Munich (TUM) believes fat derived from myelin that is not carried away rapidly enough by phagocytes can trigger chronic inflammation. This, he writes in Science, then impedes regeneration.
Professor Simons and his team discovered that the destruction of myelin crystalline cholesterol can trigger persistent inflammation, which prevents regeneration.
"Myelin contains a very high amount of cholesterol,” he said. “When myelin is destroyed, the cholesterol released has to be removed from the tissue.”
This is performed by microglia and macrophages. They take up the damaged myelin, digest it and transport the non-digestible remainder, such as cholesterol, out of the cell by transport molecules.
If too much cholesterol accumulates in the cell, cholesterol can form needle-shaped crystals, which cause damage the cell.
Prof Simons and his researchers used a mouse model to demonstrate the impact of the crystalline cholesterol.
They showed that it activates the so-called inflammasome in phagocytes, which results in the release of inflammatory mediators, attracting even more immune cells.
"Very similar problems occur in arteriosclerosis, however not in the brain tissue, but in blood vessels," he said.
The success of the microglia and macrophages depended on the age of the animal, with older ones finding it more difficult to clear cholesterol, leading to stronger the chronic inflammations.
Professor Simons said he and his team want to establish if this mechanism can be used therapeutically to promote regeneration in MS.
In another study, recently published in Science Translational Medicine, Professor Simons and Professor Christine Stadelmann, of the University of Göttingen’s Institute of Neuropathology, discovered a novel cell type of oligodendroglial – specialised glial cells that are responsible for myelination in the central nervous system.
"We believe that the BCAS1-positive oligodendrocytes that we discovered represent an intermediate stage in the development of myelin-forming cells,” explained Professor Simons.
“In humans they can only be identified for a relatively short period of time, exactly then when myelin is actually being formed. We hope that the BCAS1 positive cells will help us to identify new regenerative medicines.”
Cantuti-Castelvetri L, Fitzner D, Bosch-Queralt M et al. Defective cholesterol clearance limits remyelination in the aged central nervous system. Science 4 January 2018; doi: 10.1126/science.aan4183 [abstract]
Fard M K, van der Meer F, Sanchez P et al. BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions. Science Translational Medicine 6 December 2017; doi: 10.1126/scitranslmed.aam7816 [abstract]
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