The Mysterious Link Between Little Blobs of Brain Fat and the ‘Alzheimer’s Gene’

By | June 13th, 2024

For decades, scientists weren’t sure why microglia cells in the brains of people with Alzheimer’s were filling up with little blobs of fat. Stanford researchers just found out it might have something to do with the “Alzheimer’s gene,” APOE4.

When Alois Alzheimer first described the brains of people with Alzheimer’s disease more than 100 years ago, he spotted the telltale signs of the disease — beta-amyloid plaques and tau protein tangles — which became the focus of many researchers. 

He also made one observation that went unnoticed and unstudied for decades: In people with the disease, the brain’s immune cells — microglia — were filled with fat droplets — microscopic globs of fat smaller than the size of a cell. Fat is normally an important component of the brain: Fatty sheaths insulate nerve fibers in the brain which allows different parts of the brain to communicate. In this case, the tiny blobs of fat are sign of something going wrong. 

A new study published in Nature also focused on these culprit droplets, corroborating Alois’s early observations, and taking things a couple steps further: The scientists found that the fat droplets seem to be related to the presence of beta-amyloid, a problematic protein that builds up in people’s brains more than a decade before Alzheimer’s symptoms start. 

According to the research team, it appears these fat droplets cause the microglia — to malfunction, releasing chemicals that perpetuate damage to brain cells. And in people carrying the APOE4 genetic variant — known as the “Alzheimer’s gene” because it drives a higher risk of developing the disease — microglia seem to produce even more of these fat droplets than in people with Alzheimer’s who aren’t carriers of APOE4.

Brigham Young University professor David Hansen, who was not involved in the study, told Being Patient that the study’s results make a “compelling argument” that changes in how microglia package and move fat droplets around in the brain do have an important impact on brain health over time.

According to Hansen the results may explain how different genetic risk factors for Alzheimer’s — genes like APOE4 involved in moving fat molecules, and TREM2 which help microglia respond to damage — are related.

What the study found

The researchers first examined brain tissue from people who died of Alzheimer’s and compared it to a control group of people who died of other causes. They then isolated the immune cells (the microglia) from the brain tissue and used a technique to “spy on” what genes were turned on.

When a gene turns on, it sends a message that tells the cell to make protein machinery.  Counting the number of messages related to each gene shows researchers how much a gene is being activated. In this case, microglia from Alzheimer’s had more activation of the ASCL1 gene — which tells cells to make proteins involved in making fat droplets — than in the controls. Microglia from people with two copies of the risk gene APOE4 had the highest level of ASCL1 gene activation. 

The researchers used a technique to visualize fat droplets and spotted lots of microglia filled with fat droplets surrounding a form of beta-amyloid protein in the Alzheimer’s brain tissue. Then, researchers grew microglia in a dish. When they added amyloid to the cells, those cells began making fat droplets in response — and the cells with two copies of the APOE4 gene made the most fat droplets.

Could stopping these fat droplets treat Alzheimer’s and other age-related brain diseases?

Michael Haney, the study’s lead author and assistant professor at the University of Pennsylvania, told Being Patient that microglia might form fat droplets in response to brain damage, infection, or inflammation — not just beta-amyloid. 

According to Haney, it’s important for scientists to understand whether the fat droplets are the root cause brain injury in Alzheimer’s, or rather,  a side effect of other disease processes, whether that’s the presence of beta-amyloid or one of these other factors.

Previous studies have spotted microglia filled with fat droplets in aging brains and after strokes

It is very much an active topic of investigation,” Haney said — and more research is needed to see whether fat droplets might be involved in other diseases.

Could the findings lead to new treatments for Alzheimer’s, or even a preventive intervention? Currently, there are no drugs on the market that stop these fat droplets from forming. Haney said that since these fat droplets play important roles throughout the body, it would be hard to create a drug that doesn’t have a lot of side effects. 

“However,” he said, “I am still optimistic that future research could reveal a therapeutic window to target lipid droplet accumulation in microglia.”

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