Study highlights APOE4’s deleterious effect on lipids

UNC School of Medicine researcher Sarah Cohen, PhD, and Ian Windham, a former postdoctoral fellow in the Cohen lab, have made a new discovery about apolipoprotein E (APOE) — the biggest genetic risk factor for late-onset Alzheimer’s disease. Alzheimer’s.

Older people who inherited a genetic variant called APOE4 from their parents have two or three times the risk of developing late-onset neurodegenerative disease. If researchers can better understand how APOE4 affects brain cells, it may help them design effective therapeutics and target the mechanisms that cause the increased risk of disease.

Cohen and Windham conducted an extremely thorough, five-year study to better understand and visualize the relationship between APOE4, Alzheimer’s disease, and fat molecules called lipids in the brain.

“We found that brain cells known as astrocytes are more vulnerable to damage and may even malfunction when APOE4 surrounds their lipid storage centers,” said Cohen, assistant professor of cell biology and physiology and senior author on the paper published in Journal of Cell Biology. “This mechanism could explain exactly why APOE4 increases Alzheimer’s risk at the cellular level.”

The role of lipids in the brain

Sixty percent of the brain’s dry mass consists of lipids, which play important roles in the brain, such as storing cellular energy and forming myelin, the substance that surrounds and insulates neurons. Lipids can be found in specialized fat storage compartments known as lipid droplets within astrocytes.

As useful as they are, lipids can also become toxic if the conditions are right. When excited or stressed, neurons release toxic lipids into the environment. Astrocytes are tasked with clearing free-floating toxic lipids and preventing them from accumulating in the brain.

If the astrocytes were damaged or dysfunctional in any way, they could not perform their cleaning duties. As a result, other brain cells, called microglia, can’t even clean up amyloid beta plaques in the brain, another factor that leads to Alzheimer’s disease.

Viewing APOE in real time

APOE is produced by astrocytes. Like a taxi or Uber, the protein oversees the release and transport of lipids between cell types in the brain. Windham and Cohen wanted to see exactly what happens to lipids in astrocytes. Windham led the charge, creating a tagging and labeling system that would allow them to see the insides of astrocytes in action under the microscope.

Labeling APOE with green fluorescent protein allowed us to see the different places APOE goes while inside living cells.”

Ian Indham, now a postdoctoral fellow at Rockefeller University and first author of the paper

The team first fed astrocytes oleic acid, an omega-9 fatty acid produced naturally in the body. Using a microscope, the team observed the usual formation of lipid droplets. APOE4, surprisingly, zipped around the lipid droplets like a magnet and changed the shape and size of the droplets.

It became abundantly clear to the researchers that APOE4 can escape secretion, become locked inside astrocytes, and migrate to lipid droplets within astrocytes. Windham and Cohen hypothesized that altered lipid droplet composition could cause astrocyte dysfunction and affect the ability of microglia to clear beta amyloid.

Lipids: The next frontier

However, more research is needed to know the specifics. Cohen hopes their findings will further highlight the role of lipid droplets in Alzheimer’s disease and other neurodegenerative diseases.

“In Alois Alzheimer’s first paper, he described three hallmarks of neurodegenerative disease: amyloid beta plaques, tau tangles, and lipid accumulations,” Cohen said. “The first two have gotten a lot of attention. The next frontier is lipids. With APOE being the biggest genetic risk factor, we think it holds the clues to how lipids fit into the story.”