Cholesterol medications might be able to be repurposed for MS: Study
Brain stem cells boost cholesterol production in MS, driving neurotoxic damage
Increased production of cholesterol by stem cells in the brain contributes to neurological damage in multiple sclerosis (MS), according to a new study conducted in lab-grown cells.
Findings suggest cholesterol-lowering medications can reverse this damage, implying such treatments might be able to be repurposed for MS.
“Cholesterol metabolism has been extensively investigated in the context of non-communicable diseases, such as cardiovascular disease, and more recently, in cancer,” Angelo D’Alessandro, PhD, a professor at the University of Colorado School of Medicine and co-author of the study, said in a university news story. “Common drugs that target cholesterol metabolism have been proven to be safe and effective in humans. Our findings suggest that these drugs could be repurposed in the treatment of MS.”
The study, “Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis,” was published in Cell Stem Cell.
In MS, inflammation in the brain causes damage to nerve cells, and this neurological damage ultimately drives disease symptoms.
In theory, activating neural stem cells could help repair damage that drives MS
The brain houses stem cells, called neural stem/progenitor cells or NSCs, that are able to grow into new healthy nerve cells. In theory, activation of these cells could help repair the damage that drives MS. However, NSCs in MS tend to be in a state of senescence, which basically means that the cells are inactive, so their ability to repair damage is blunted.
The reasons for NSC senescence in MS are poorly understood, but finding ways to turn off senescence and activate these stem cells might be a viable strategy for developing new MS treatments.
In the study, a team of scientists set out to better understand the mechanisms that drive senescence in MS NSCs. For their experiments, the researchers engineered skin cells from people with progressive forms of MS into NSCs, and other NSCs were derived from people without MS to be used as controls. As expected, the MS NSCs showed increases in markers of cellular senescence.
Through a battery of experiments, the researchers determined the senescent MS NSCs were in a hypermetabolic state, meaning they were burning more sugar than is typical. In addition to using the sugar for energy, the cells were using byproducts from the sugar to produce high levels of cholesterol and other fatty molecules.
Additional experiments revealed the excessive cholesterol was activating senescence-promoting proteins in the NSCs. In addition to driving senescence in the cells themselves, this also led to a characteristically senescent collection of molecules the cells were secreting to communicate with other cells, known as the secretome. The senescent secretome could cause damage to neighboring nerve cells, results showed.
Cholesterol-associated secretomes contribute to neurotoxic damage in MS
“Our study identifies cholesterol-associated secretomes as key contributors to neurotoxic damage in progressive MS,” said Stefano Pluchino, MD, PhD, study co-author at the University of Cambridge.
Based on these findings, the researchers predicted that treatment with a cholesterol-lowering medication might act to reduce senescence in MS NSCs and improve the health of nearby nerve cells. Indeed, treatment with simvastatin — a type of cholesterol-lowering drug called a statin — was shown to have nerve-protecting properties in the cell models.
“Our findings suggest a disease-associated, cholesterol-related, hypermetabolic [status of NSCs derived from MS patients] that leads to neurotoxic signaling and is rescuable pharmacologically,” the scientists concluded.
Pluchino said these findings offer “opportunities for precise interventions in previously overlooked brain cell subsets, including neural stem/progenitor cells.”
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