Alzheimer's disease: Tau proteins aggregate to neurofibrillary tangles and neuritic plaques in a neuron axon
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Researchers at Washington University School of Medicine in St. Louis have discovered that a type of brain cholesterol, specifically cholesteryl esters, could be a key factor in preventing brain damage and behavioral changes associated with the overaccumulation of tau protein in the brain associated with Alzheimer’s disease.

In Alzheimer’s disease, cognitive decline is closely linked to the abnormal buildup of tau protein. As tau accumulates, nearby brain tissue begins to degenerate and die, leading to the devastating effects of the disease. Reporting in Neuron, scientists have now uncovered that tau deposits in the brain trigger the accumulation of cholesteryl esters. Lowering cholesteryl ester levels in mice, in turn, proved effective in preventing both brain damage and behavioral changes resembling those seen in Alzheimer’s disease.

“The compound we used in this study has side effects that make it unsuitable for use in people. But if you could develop a therapy that reduces cholesteryl esters inside brain cells without unacceptable side effects, it would be a promising candidate to test in neurodegenerative diseases,” explained David Holtzman, MD, scientific director at the Hope Center for Neurological Disorders and senior author of the study.

The connection between cholesterol and dementia may not be as surprising as it seems. A gene called APOE, known to be the biggest genetic risk factor for Alzheimer’s, is involved in both activating the brain’s immune cells and carrying cholesterol and other lipids in the blood. The researchers investigated mice with a high-risk tau gene predisposing them to tau accumulation. The study also involved variations of the APOE gene, including APOE3 and APOE4, which respectively confer an average and elevated risk of Alzheimer’s.

According to the researchers, APOE4 is linked to a distorted lipid metabolism in the brain. Mice with APOE4 showed excess lipids in brain areas prone to atrophy and damage, particularly cholesteryl esters accumulating in microglia, immune cells in the brain. In contrast, APOE3 did not produce the same effect.

To test the potential of reducing brain inflammation and neurodegeneration, the researchers used an experimental drug called GW3965, which enhances the effects of  a receptor known as liver X receptor (LXR), ultimately leading to lower lipid levels in cells. The drug was administered to tau mice carrying APOE4, resulting in significant outcomes. Mice that received the drug exhibited retained brain volume, lower tau levels, reduced inflammation, fewer inflammatory cells, and improved cognitive functions compared to those given a placebo.

The drug achieved its effects by upregulating a gene called Abca1, responsible for moving cholesterol and other lipids out of cells. Increasing Abca1 levels through genetic methods produced similar positive outcomes, further supporting the potential therapeutic value of this approach.

While the study showcased promising results, one significant obstacle remains – the side effects of LXR agonists on liver lipid metabolism. Holtzman acknowledged this challenge, stating that researchers are working to design LXR agonists without these undesirable side effects. If successful, these drugs could have dual benefits for both brain and heart health, addressing lipid accumulation issues in conditions like Alzheimer’s and atherosclerosis.

“There’s a lot of similarity between the mechanism that’s driving immune cells to damage the brain in Alzheimer’s disease and the one that’s driving the same kinds of immune cells to cause vascular damage in atherosclerosis. In both cases, lipids accumulate in immune cells, causing them to become hyperinflammatory and damage nearby tissues. Getting rid of that lipid accumulation may have double benefits for human health,” Holtzman concluded in a press statement.

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