Lowering cholesterol esters protects the brain from Alzheimer’s-like damage

In Alzheimer’s disease and related dementias, cognitive decline is caused by the over-accumulation of a normal brain protein known as tau. Where tau accumulates, nearby brain tissue begins to degenerate and die.

Now, researchers at Washington University School of Medicine in St. Louis have discovered—in mice—that Alzheimer’s-type deposits in the brain lead to the accumulation of a form of cholesterol known as cholesterol esters, and that lowering cholesterol levels helps prevent brain damage and behavioral changes. .

This has important therapeutic implications. The compound we used in this study has side effects that make it unsuitable for use in humans. But if you could develop a treatment that reduces cholesterol esters inside brain cells without unacceptable side effects, it would be a promising candidate for testing in neurodegenerative diseases.”

David M. Holtzman, MD, Senior Author, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology

The findings are published Nov. 22 in the journal Neuron.

The link between cholesterol and dementia is not as far-fetched as it may seem. The biggest genetic risk factor for Alzheimer’s is APO, a gene involved in the activation of immune cells in the brain. When such cells are activated in the wrong way or at the wrong time, they can damage brain tissue. But APOE also has another important job in the body: It transports cholesterol and other lipids in the blood. In this capacity, it plays a role in atherosclerosis.

To investigate the connections between APOE, lipids, and brain damage, Holtzman and first author Alexandra Litvinchuk, PhD, a postdoctoral researcher, studied mice with a high-risk tau gene that predisposes them to accumulate tau in their brains. Such mice begin to develop signs of neurodegeneration around 6 months of age. By 9½ months, their brains are severely damaged and they are no longer able to complete normal mouse life tasks, such as building a nest properly. The mice also carried a second genetic modification: their own APO genes had been removed and either replaced with a human variant APO gene – APOE3, which carries an average risk for Alzheimer’s. the APOE4that doubles or triples Alzheimer’s risk — or is not replaced at all.

The survey revealed that APOE4 associated with distorted lipid metabolism in the brain. In 9 ½-month-old tau-carrying mice APOE4, the same regions of the brain that were atrophied and damaged also accumulated excess lipids and in a strange pattern. Levels of more than 180 lipid species were altered. Among the most striking differences was that the immune cells known as microglia in these areas were filled to the brim with cholesterol esters. APOE3 it didn’t have the same effect. The measurement of brain lipids was done in collaboration with Denali Therapeutics scientists led by Gilbert Di Paolo, PhD.

“Microglia loaded with lipids become hyper-inflammatory and start secreting things that are not good for the brain,” Holtzman said.

Therefore, removing lipids could potentially reduce brain inflammation and neurodegeneration, he said. To find out, Litvinchuk and Holtzman used an LXR agonist, a member of an experimental class of drugs that lower lipid levels in cells. The researchers fed the drug, called GW3965, to tau-bearing mice APOE4, starting at the age of 6 months. The mice were evaluated at 9 ½ months, by which time their brains would normally have suffered significant damage. Mice given the drug retained significantly more brain volume than those given a placebo. They also had lower tau levels, fewer inflammatory cells and less inflammation, less loss of synapses in their brains, and were better at building nests.

Further research revealed that the LXR agonist works by upregulating a gene called Abca1 which helps remove cholesterol and other lipids from cells. Using genetic methods to increase Abca1 levels had the same effect as drug treatment: less lipid accumulation, lower tau levels, less inflammation and reduced neurodegeneration.

“What’s exciting is that we see all these results in an animal model that shares many features with human neurodegenerative diseases,” Holtzman said. “It shows that this kind of approach could hold a lot of promise.”

A major hurdle stands in the way of translating this approach to humans, Holtzman added. LXR agonists also affect lipid metabolism in the liver and thus tend to cause fatty liver disease. Chemists are trying hard to design LXR agonists without this side effect. If successful, the resulting drugs may have benefits for heart disease as well as brain disease.

“There is a great deal of similarity between the mechanism that drives immune cells to damage the brain in Alzheimer’s disease and the mechanism that drives the same types of immune cells to cause vascular damage in atherosclerosis,” Holtzman said. “In both cases, lipids build up in immune cells, causing them to become hyper-inflammatory and damage nearby tissues. Getting rid of this lipid build-up can have dual benefits for human health.”