In a groundbreaking discovery, researchers at the University of Colorado Anschutz Medical Campus, in collaboration with colleagues at the University of Cambridge, have found that when the body makes more cholesterol, it can be harmful to brain cells in people with progressive multiple sclerosis (MS). This suggests that higher cholesterol production may contribute to the worsening of the disease by damaging the nervous system.
The study was published today in Cell Stem Cell.
The research team created a model using cells grown in the lab to better understand progressive MS. They took skin cells from patients and transformed them into brain-like cells, which helped them discover a new problem in how these cells use energy that makes the MS worse. The finding could lead to new treatment options for the disease.
MS is a chronic neurological disease impacting over 2 million people globally. It occurs when the immune system mistakenly attacks the myelin sheath protecting nerve fibers, leading to the progressive loss of neurons and resulting in both physical and cognitive disabilities. This neuronal degeneration, rather than just the loss of myelin, is central to the irreversible worsening of symptoms over time. In advanced stages, the interplay between aging and MS becomes more pronounced, indicating that age-related changes may intensify neuronal loss.
Despite treatment advancements, current therapies primarily manage symptoms without halting or reversing neurodegeneration. This highlights the urgent need for deeper insights into disease progression – by using patient-derived tools and innovative stem cell technologies for MS modeling.
The study is being led by Angelo D’Alessandro, PhD, professor of biochemistry and molecular genetics at the University of Colorado School of Medicine, and University of Cambridge professors Stefano Pluchino, MD, PhD, and Rosana-Bristena Ionescu, PhD, and post-doctoral researcher Alexandra M. Nicaise.
Statin can lower harmful cholesterol
The reported findings shed light on a condition called cellular senescence, which has been seen in certain brain cells. This state can make it harder for the brain to heal and can worsen damage in progressive MS. The researchers found that in brain-like cells from MS patients, there’s a problem with how the cells handle energy, leading to too much cholesterol. This extra cholesterol creates harmful substances that damage nerve cells. They discovered that simvastatin, a common drug that lowers cholesterol, can help improve this harmful process and create a healthier environment for the cells.
“Cholesterol metabolism has been extensively investigated in the context of non-communicable diseases, such as cardiovascular disease, and more recently, in cancer,” said D’Alessandro, co-senior author on the study. “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 researchers say this work confirms the close relationship between cellular aging (senescence) and problems with how cells use energy (dysmetabolism). The results show how cells manage fats, including cholesterol, is important for the way they communicate with each other to function properly.
Cholesterol causes neurotoxic damage
“Our study identifies cholesterol-associated secretomes as key contributors to neurotoxic damage in progressive MS. Excitingly, we show that these intrinsic cell dysfunctions can be targeted pharmacologically, offering opportunities for precise interventions in previously overlooked brain cell subsets, including neural stem/progenitor cells,” said Pluchino, the lead and co-senior author of the paper.
The team believes this discovery paves the way for new treatments focused on how the body processes cholesterol. By targeting cholesterol metabolism, they hope to reduce nerve damage and slow down the progression of multiple sclerosis (MS).
This ultimately highlights how using patient-derived cells can help researchers understand the disease better and identify new factors that affect its progression. It’s an approach that could lead to finding new targets for treatment, offering hope for future therapies.
