A cholesterol drug that reduced brain damage in mice could reveal a new approach to treating Alzheimer’s disease in people.
The challenge: More than 6 million people in the US live with Alzheimer’s, an incurable, progressive brain disease that leads to problems with memory and cognition. Every year, 120,000 Americans die from it, making it one of the nation’s leading causes of death.
While there’s still a lot we don’t understand about Alzheimer’s, two things we do know are that it appears to be driven, in part, by a build-up of improperly folded tau proteins in the brain and that people with one common variant of the APOE gene — which helps transport cholesterol and other lipids throughout the body — are at much higher risk of developing the disease.
More than 6 million Americans live with Alzheimer’s, and 120,000 die because of it every year.
By building off these two bits of knowledge, researchers at Washington University in St. Louis (WUSTL) have now discovered a way to reduce Alzheimer’s-like brain damage in mice.
The study: There is no perfect mouse model of Alzheimer’s, but there are mice that are genetically predisposed to accumulate tau in their brains. This starts to cause neurodegeneration when the rodents are about 6 months old, and by the age of 9.5 months, they have severe brain damage and are unable to complete common mouse tasks, like nest building.
For their study, the WUSTL team tested three versions of these tau mice.
One group had their APOE genes replaced with human APOE4 genes — that’s the variant that drastically increases a person’s risk of developing Alzheimer’s. Another group had their APOE genes replaced by the human APOE3 gene — that variant doesn’t affect a person’s risk of Alzheimer’s — and the final group retained their original APOE genes to serve as controls.
The results: By 9.5 months old, mice with the APOE4 gene had abnormal levels of 180 lipids in the damaged parts of their brains, and their brain immune cells, called “microglia,” were packed with the lipids.
“Microglia filled up with lipids become hyperinflammatory and start secreting things that are not good for the brain,” said senior author David M. Holtzman.
These changes didn’t occur in mice with the APOE3 variant.
“We see all these effects in an animal model that shares a lot of features with human neurodegenerative diseases.”
David M. Holtzman
The treatment: The researchers then decided to see what would happen if they started giving mice with the human APOE4 variant an experimental type of drug, called an LXR agonist, designed to lower lipid levels in cells.
At 9.5 months, after about 3.5 months of treatment, the mice had lower levels of tau, less inflammation, and fewer inflammatory cells in their brains than those fed a placebo. They lost less brain volume, retained more brain synapses, and were better at building nests, too.
Looking ahead: The LXR agonist might have improved the rodents’ brain health, but an unfortunate side effect of these drugs is that they tend to cause fatty liver disease, which currently makes them unsuitable for people.
Still, researchers are working to develop LXR agonists that are safe for humans, and even if those particular meds aren’t the answer, the new WUSTL study has shown that lowering lipid levels in the brain is a viable new target for treating Alzheimer’s.
“What’s exciting is that we see all these effects in an animal model that shares a lot of features with human neurodegenerative diseases,” said Holtzman. “It shows that this kind of approach could have a lot of promise.”
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