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

Evan Walker
Evan Walker TheMediTary.Com |
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Clearing cholesterol ester-buildup from the brain could help prevent diseases like Alzheimer’s. undefined undefined/Getty Images
  • 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 brainamyloid 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.

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.”

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