ARTICLE IN BRIEF
Two different animal studies uncovered insights into cholesterol's role in MS — one, by looking at its role in limiting remyelination in the aged central nervous system, and the other by looking at how targeting genes for cholesterol synthesis could diminish MS symptoms.
Two new animal studies implicate cholesterol as a key player in multiple sclerosis (MS).
In one study, published online January 4 in Science, a team of German scientists discovered a cholesterol clearance problem in aging animals after acute trauma: Macrophages had trouble clearing away myelin debris (enriched in cholesterol) and it led to an accumulation of cholesterol crystals that induced a chronic inflammatory response that impaired remyelination.
In the other study, scientists at the University of California, Los Angeles (UCLA) looked at gene expression in specific cells and in different regions impacted by MS, finding that the most robust changes were decreases in expression of cholesterol synthesis genes in astrocytes in the spinal cord and in the optic nerve. The study, conducted in the most commonly used MS animal model — experimental autoimmune encephalomyelitis (EAE) — was published in the January 9 online edition of The Proceedings of the National Academy of Sciences (PNAS).
“These studies point to cholesterol's importance in the central nervous system [CNS],” said the PNAS senior study author Rhonda R. Voskuhl, MD, professor of neurology at UCLA and the Jack H. Skirball Chair for Multiple Sclerosis Research and director of the UCLA Multiple Sclerosis Program.
DEFECTIVE CHOLESTEROL CLEARANCE
In the Science study, Mikael Simons, PhD, co-director of the Institute of Neuronal Cell Biology at Technical University of Munich, and his colleagues asked a simple question: Is there a difference in the recovery of young and old animals following an acute demyelinating injury? What scientists know about MS is the disease progresses as they get older.
The investigators delivered a single injection of a toxin (lysolecithin) into the white matter or into the spinal cord, which caused a focal demyelinating lesion. Demyelination was complete in four days, and then the animals began to repair the damage by clearing out the debris to make way for remyelination. They compared the time to remyelination in three-month old animals and 12-month animals.
Cholesterol is one of the main components of myelin. When myelin breaks down in response to trauma or disease, the immune system sends in phagocytes to clear out the debris. The phagocytes must metabolize the cholesterol and then transport it out of the cells onto lipoprotein particles.
The investigators found that the older animals were accumulating cholesterol crystals in phagocytes and activating the so-called inflammasome, resulting in the release of inflammatory mediators, and attracting even more immune cells. They believe that the immune cells that were called in set off a chronic inflammatory response that impairs remyelination. However, when old animals were treated with drugs that prevent cholesterol crystal build-up and stimulate reverse cholesterol transport, the clearance pathway returned to its youthful cholesterol-clearing vigor. Thus, clearance of cholesterol from phagocytes appears to be the bottleneck for the repair process in aging animals, they proposed.
The scientists are now looking to see whether this same mechanism exists in MS patients as they age.
CHOLESTEROL AND ASTROCYTES IN MS
The fact that MS patients have such diverse disabilities prompted Dr. Voskuhl to think about why patients differ so much from one another, particularly early in disease.
“Some patients have primarily visual problems, and others [have problems with] walking or cognition,” she explained. “There has been a one-size-fits-all approach to targeting disabilities in MS, which has not led to treatments that can repair disabilities, so we need new ways of tackling this disease.”
In their latest study in PNAS, her team looked at gene expression in different cell types and different regions of the brain in the EAE model that could help explain the wide range of disabilities among patients.
The researchers compared gene expression in astrocytes in five different vulnerable regions in the EAE animal model and found region-specific differences in gene expression in astrocytes. They discovered dramatic reductions in the expression of genes for cholesterol synthesis in the spinal cord and the optic nerve, with an intermediate decrease in the cerebellum, and no decreases in the hippocampus or cerebral cortex.
These genetic differences were intriguing, especially since all five of these regions have neuropathology in the EAE animal. In contrast, they also reported increases in inflammatory genes in astrocytes; the optic nerve had some unique increases compared with the spinal cord, further suggesting selective targeting of treatments for vision versus walking.
The group hypothesized that cholesterol made in the brain is critical for repairing the damage seen in MS. Cholesterol can be made by many cell types, they explained, including oligodendrocytes, neurons, and astrocytes. By adulthood, only astrocytes make cholesterol. Astrocytes make it for transport out to neurons and oligodendrocytes. Neurons need the fatty substance to make synapses. And oligodendrocytes need cholesterol to make myelin.
They wanted to see whether targeting genes for cholesterol synthesis would diminish symptoms in the EAE animals. The team used a nuclear receptor agonist that binds to the ATP-binding cassette transporter (ABCA1) of cholesterol out of cells.
“The EAE animals had significant paralysis, but treatment with the agonist dramatically improved walking,” said Dr. Voskuhl. Behind the scenes, agonist treatment increased cholesterol synthesis gene expression by more than 50 percent in the spinal cord, making more available for transport to neurons and oligodendrocytes for repair.
“This drug was repairing the damage seen in the EAE model,” Dr. Voskuhl added. “Astrocytes can make cholesterol (in adults) during injury to repair the damage.” She added that they would never have observed cholesterol's role in MS had they not conducted cell-specific and region-specific transcriptomic testing.
The team also found abnormal cholesterol synthesis gene expression in autopsied optic nerve tissue collected from MS patients.
“This is a very exciting new way to address questions the field has had about how to find neuroprotective treatments for the many different disabilities that vary from person to person with MS,” said Dr. Voskuhl. “By extending this approach to other cells and other regions, treatments can now be discovered that are tailored for each disability, one at a time. Further, this disability specific approach is not limited to MS, but can be implemented in other complex neurodegenerative diseases.”
“Identifying cholesterol clearance as a remyelination mechanism is an important addition to our understanding of how the immune system regulates myelin repair,” said Katerina Akassoglou, PhD, senior investigator at the Gladstone Institute of Neurological Disease and professor of neurology at the University of California, San Francisco. “We think of cholesterol clearance working in the periphery, but this mechanism also is taking place in the brain, and now these scientists are showing that impaired clearance of cholesterol affects remyelination in the aging brain.”
Commenting on the paper in Science, she added: “We did not know that cholesterol crystals accumulate in the brain. We need to know whether this cholesterol build-up and an inability to clear it away is a component in MS patients and in others with demyelinating conditions. The findings give us a nice direction to explore human relevance.”
“These are important studies that advance the field,” added Bibi Bielekova, MD, chief of the neuroimmunological diseases unit at the National Institute of Neurological Disorders and Stroke. “Treatments that target this pathway may be useful in speeding up remyelination.”
“In multiple sclerosis, inflammation can arise at any point within the CNS, resulting in demyelination and axonopathy,” said Benjamin M. Segal, MD, director of the Multiple Sclerosis Center and the Holtom-Garrett Program in Neuroimmunology at the University of Michigan. “Dr. Voskuhl and her colleagues hypothesize that inflammation during MS suppresses cholesterol synthesis in astrocytes, thereby interfering with endogenous repair pathways. This concept is novel and holds important translational implications for future MS therapies.”
“The current paper adds to a growing body of evidence that the same cell type can have distinct biological functions in different regions of the central nervous system,” he added. “In some people with MS, lesion burden is concentrated in a CNS compartment (for example, the cervical spinal cord, the cerebral white matter, or even in the cortex). Future MS therapies may need to be customized based on the spatial distribution of lesions in an individual patient.”
“MS lesions can affect any part of the brain and spinal cord,” added Suhayl S. Dhib-Jalbut, MD, FAAN, professor and chairman of neurology and director of the Robert Wood Johnson Center for Multiple Sclerosis at Rutgers University. “The findings in the animal model are exciting, but it will be a real challenge in clinical practice to identify regional and cell-specific pathways responsible for patient's symptoms. The approach is novel and could ultimately lead to drugs that improve the clinical outcome for patients. The question remains as to whether the regional and cell-specific alterations are primary or secondary to the inflammation.”
The study authors and commentators had no disclosures related to the current study.