Cholesterol buildup in brain presents new target to reduce dementia risk from stroke

Jan. 27, 2022

University of Arizona Health Sciences researchers suggest stroke recovery might be improved by a drug that could help immune cells process the cholesterol-rich debris generated by a stroke.

The study was published in the Journal of Neuroscience and described in a news release from University of Arizona Health Sciences.

Researchers at the University of Arizona College of Medicine — Tucson and the U Arizona R. Ken Coit College of Pharmacy have discovered a potential treatment to reduce the risk of post-stroke dementia, which may be influenced by the immune response to dead brain tissue left in the wake of a stroke.

Ischemic strokes occur when blood vessels to the brain are blocked or restricted, cutting off the brain’s supply of oxygen and nutrients, and killing brain cells. The resulting patch of dead tissue sets off an inflammatory response that can last for months as the immune system struggles to processes the cholesterol-rich debris that is primarily composed of myelin, a fatty substance that forms an insulating sheath around neurons. Inflammation is a normal part of the immune response in which immune cells rush to the site of injury, but it can damage tissue if it lasts too long.

“Up to one-third of people who have a stroke develop dementia in the months afterward. We don’t know what causes that,” said Kristian Doyle, PhD, Associate Professor of Immunobiology and Neurology at the College of Medicine-Tucson. “We’re testing the hypothesis that dementia could be caused by a lingering, smoldering inflammatory response at the site of the stroke, causing further damage to neighboring brain regions.”

Most stroke research focuses on the first few hours, when the brain is deprived of its blood supply and cells start dying. In contrast, Doyle focuses on the weeks and months after a stroke, leading him into largely uncharted territory. Recovery from stroke is not well studied and little is known about how dementia develops in its wake. For some, it might be triggered by subsequent strokes or other conditions like Alzheimer’s disease. But in others, Doyle suspects dementia arises when the immune system is overwhelmed by the fatty mess created by dead brain tissue.

The Doyle Lab previously discovered that, after a stroke, the inflammatory response to the dead brain tissue spreads into healthy areas of the brain, killing more brain cells.

Doyle’s team is investigating 2-hydroxypropyl-β-cyclodextrin, or cyclodextrin, a molecule they hope will help the immune system clear the cholesterol-rich stroke debris with less collateral damage. They are exploring whether the inflammatory response is exacerbated by cholesterol, which is rapidly dumped into the brain as dead cells break down. Immune cells take in this cholesterol at such high concentrations that crystals form inside them, causing further damage and sounding the alarm for more immune cells to respond.

Thanks to cyclodextrin’s chemical properties and barrel shape, cholesterol can be safely stored within the “barrel” without provoking a heightened inflammatory response. Doyle’s team found that treatment with cyclodextrin resulted in less cholesterol accumulation and inflammation in the brain in animal models. Cyclodextrin also reduced neurodegeneration, protected memory function and reduced impulsivity, a personality change that can occur after stroke.

Cyclodextrin is currently FDA approved as an ingredient in other drugs, though it is not used as a standalone treatment. Instead, Doyle says it’s used as a “vehicle” to deliver drugs to hard-to-reach places, transporting active ingredients in its protective, barrel-shaped container.

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