Study: Cholesterol in Brain Associated Alzheimer Disease, Brain Damage

Alzheimer-like tau deposits have led to more accumulation of cholesteryl esters, and investigators believe that lowering cholesteryl ester levels could help prevent brain damage and behavioral changes, according to results of a study published in Neuron.^1,2

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“This has important therapeutic implications,” David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology at the Washington University School of Medicine in St. Louis, said in a press release. “The compound we used in this study had [adverse effects (AEs)] that make it unsuitable for use in [humans]. But if you could develop a therapy that reduces cholesteryl esters inside brain cells without unacceptable [AEs], it would be a promising candidate to test in neurodegenerative diseases.”¹

In the study, investigators aimed to determine whether there was an association between the APOE gene, lipids, and brain damage. APOE activates the brain’s immune cells, but it can also carry cholesterol and other lipids through the blood. The gene is also known to be the biggest genetic risk factor for Alzheimer disease (AD). The study investigators used mice with a high-risk tau gene, predisposing the mice to tau accumulation in the brain. The mice also had a second genetic modification, which removed the mice version of APOE and replaced it with either the human versions of the gene APOE3 or APOE4. The 2 genes predict the risk of AD with APOE3 being average risk and APOE4 doubling or tripling the risk. Additionally, some mice did not have their gene replaced.¹

The study investigators found that APOE4 was linked to lipid metabolism in the brain of the mice carrying the gene. They also found that that area of the brain became damaged due to the excess lipids. They altered more than 180 different kinds of lipids, finding that microglia, a type of immune cell, were filled with cholesteryl esters. Furthermore, APOE3 did not have the same affect, according to the investigators.¹

“Microglia filled up with lipids become hyperinflammatory and start secreting things that are not good for the brain,” Holtzman said in the statement. “What’s exciting is that we see all these effects in an animal model that shares a lot of features with human neurodegenerative diseases . . . It shows that this kind of approach could have a lot of promise.”¹

Holtzman added that clearing these lipids from the brain could reduce brain inflammation. He and other investigators used an LXR agonist designed to lower lipid levels in cells, according to the press release. The investigators administered the drug, GW3965, to mice who had the APOE4 gene, starting at age 6 months. Typically, by 9.5 months, the brains of the mice would have sustained considerable damage; however, the mice that received the drug retained more brain volumes than the ones that received the placebo.¹

Furthermore, the treated mice also had lower levels of tau, fewer inflammatory cells, less inflammation, and less loss of synapses in the brain. The mice were also better at building nests, according to the results. The LXR agonist also worked to help up regulate Abca1, which helps to move cholesterol and lipids out of the cells. Increasing the Abca1 levels also had the same effect as the treatment drug.¹

However, the LXR agonists can also affect lipid metabolism in the liver, causing fatty liver disease. Although the drug is currently not suitable for humans due to the AEs, investigators are working to design a drug without these concerns.¹

“There’s a lot of similarity between the mechanism that’s driving immune cells to damage the brain in [AD] and the one that’s driving the same kinds of immune cells to cause vascular damage in atherosclerosis,” Holtzman said in the press release. “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.”¹

References

1. Lowering a form of brain cholesterol reduces Alzheimer’s-like damage in mice. News release. EurekAlert. November 22, 2023. Accessed November 28, 2023. https://www.eurekalert.org/news-releases/1008647
2. Litvinchuk A, Suh JH, Guo JL, et al. Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist. Neuron. 2023. doi:10.1016/j.neuron.2023.10.023