Could lowering brain cholesterol reduce Alzheimer’s-like damage?

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  • In Alzheimer’s disease, a buildup of tau protein leads to the death of brain tissue.
  • New research has linked this tau buildup to the accumulation of cholesteryl esters — a form of lipid that is associated with inflammation.
  • The findings suggest that clearing out these cholesteryl esters may reduce the brain damage and behavioral changes seen in people with Alzheimer’s, at least in mice so far.
  • However, the researchers emphasize that the compound used in their study is unsuitable for use in people, so they are looking for other therapies that have the same clearing effect.

Alzheimer’s disease is the most common form of dementia, affecting more than 6 million people in the United States. Alzheimer’s and other dementias impact close to 60 million people worldwide. These numbers are continuing to rise, and experts estimate that by 2050, there will be more than 150 million people with Alzheimer’s and other dementias around the globe.

Symptoms of Alzheimer’s, such as memory loss, confusion, and personality changes, are thought to be largely due to an abnormal buildup of two proteins in the brain — amyloid beta and tau. These proteins form plaques and tangles that damage and eventually destroy nerve cells in the brain. However, what causes the buildup is still the subject of research.

Now, a study in mice from researchers at Washington University School of Medicine in St. Louis has found that tau deposits in the brain are linked to the buildup of a form of cholesterol. When the mice were treated to reduce these cholesteryl esters, their brain damage and behavioral changes also reduced.

The research is published in the journal Neuron.

Apolipoprotein E (ApoE) is a protein in the brain. It helps regulate the transport of cholesterol and other types of fat in the blood. There are several forms, or alleles, of the APOE gene that controls the production of this protein.

  • APOE ε2 may provide some protection against Alzheimer’s. Roughly 5% to 10% of people have this allele, which may delay the onset of, or even prevent, Alzheimer’s.
  • APOE ε3 is the most common allele. It has no impact on Alzheimer’s risk.
  • APOE ε4 increases the risk for Alzheimer’s and is associated with earlier age of disease onset. About 15% to 25% of people have this allele, and 2% to 5% carry two copies. Having two copies of this allele increases the risk of developing Alzheimer’s more than having one.

The researchers carried out the current study in mice that had been genetically engineered to accumulate tau protein in their brain. By the age of 6 months, these mice started to develop signs of neurodegeneration, and at 9.5 months, they had severe brain damage and were unable to carry out usual mouse activities, such as nest building.

They further modified the mice by removing their APOE genes. They either replaced them with human APOE ε3 or APOE ε4 — or did not replace them.

“This interesting research further elucidates the intricate link between Apolipoprotein E4 (ApoE4), a significant genetic risk factor for Alzheimer’s disease, lipid accumulation and tau pathology, in a mouse model. Discovering potential therapeutic approaches, such as enhancing glial lipid efflux, holds promise for specific interventions in Alzheimer’s, offering hope for effective treatments.”
— Dr. Emer MacSweeney, CEO and Consultant Neuroradiologist at Re:Cognition Health, who was not involved in the study.

In the mice with the APOE ε4 allele, areas of the brain that were damaged also accumulated fatty material, particularly cholesteryl esters. Most of this fatty buildup was in microglia — immune cells in the brain.

When microglia accumulate a lot of lipids, they start to function abnormally. They lose their ability to carry out phagocytosis (engulfing and destroying damaged tissue or pathogens), and they release pro-inflammatory cytokines, increasing inflammation in the brain.

“Microglia filled up with lipids become hyperinflammatory and start secreting things that are not good for the brain.”
— Dr. David M. Holtzman, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology, Washington University in St. Louis, and senior author of the study.

The researchers used an LXR agonist — one of an experimental class of drugs that lowers lipid levels in cells — to try to reduce inflammation and neurodegeneration in the mice.

Starting when the tau mice were six months old — the age at which neurodegeneration usually starts — scientists gave them the drug. Following the treatment, when the mice were 9.5 months old, they assessed them.

At 9.5 months, the mice that had been given the drug had significantly more brain volume than those that had received a placebo. In addition, they had lower levels of tau protein, fewer inflammatory cells, less inflammation, and less loss of synapses in their brains. They also retained their ability to build nests better than the mice given placebo.

On further investigation, the researchers found that the LXR agonist upregulates a gene called Abca1 that helps move cholesterol and other lipids out of cells.

“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,” Dr. Holtzman said.

And this approach might benefit more than the brain, as Dr. MacSweeney told Medical News Today:

“Given the similarity between the mechanism driving the lipid-filled immune cells to damage the brain and the mechanism driving lipid-laden immune cells to cause vascular damage in atherosclerosis, a medication that could remove the lipid in both of these cells could have a double effect, benefiting the brain, heart, and blood vessels.”

Although this study shows potential, the treatment cannot be used in people as it has severe side effects. LXR agonists affect lipid metabolism in the liver and can cause fatty liver disease.

“The next phase requires a solution to render this potential type of treatment not toxic to the liver in humans,” Dr. MacSweeney told MNT.

“This could, in turn, pave the way for early human studies to discover if this early work in mice could result in a particularly sought-after treatment for people with the Apolipoprotein E4 gene, who carry the highest risk of developing Alzheimer’s disease between the ages of 65–85. And all those suffering from Alzheimer’s disease and maybe also atherosclerosis,” she added.

One alternative could be genetic methods. The research found that increasing Abca1 levels had the same effect as drug treatment: less lipid accumulation, lower levels of tau, less inflammation, and reduced neurodegeneration.

“I think a gene therapy that increased Abca1 in the brain could have similar lipid-clearing effects,” Dr. Holtzman said.

“It’s an exciting time for Alzheimer’s research as we gain more insight into the disease and treatment pathways,” Dr. MacSweeney added.

Read the full article here

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