Study pinpoints APOE4’s harmful effect on lipids

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UNC School of Medicine researchers Sarah Cohen, PhD, and Ian Windham, a former PhD student in the Cohen lab, have made a new discovery about apolipoprotein E (apoE) – the largest genetic risk factor for late-onset Alzheimer’s disease.

Older people who inherited a genetic variant called APOE4 from their parents have a two- or threefold increased risk of developing late-onset neurodegenerative disease. If researchers can better understand how APOE4 is affecting brain cells, it could help them design effective therapeutics and target mechanisms that lead to increased disease risk.

Cohen and Wyndham conducted an exceptionally 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 discovered that brain cells known as astrocytes are more vulnerable to damage and can even become dysfunctional when APOE4 surrounds their lipid storage centers,” said Cohen, assistant professor of cell biology and physiology and senior author of the paper. Journal of Cell Biology. “This mechanism may explain why exactly APOE4 increases one’s risk of Alzheimer’s at the cellular level.”

Role of lipids in the brain

60 percent of the brain’s dry mass is made up 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 are found within astrocytes in specialized fat deposits known as lipid droplets.

As helpful as they can be, 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 their accumulation in the brain.

If astrocytes become damaged or dysfunctional in some way, they cannot perform their cleaning duties. As a result, other brain cells known as microglia can’t clear the brain of amyloid beta plaques, another driver of Alzheimer’s disease.

View APOE in real-time

APOE is produced by astrocytes. Much like a taxi or Uber, the protein oversees the release and transport of lipids between cell types in the brain. Wyndham and Cohen wanted to see exactly what happened to the lipids in astrocytes. Windham led the charge, developing a labeling and tagging system that allowed them to see the insides of astrocytes under the microscope.

Tagging APOE with green fluorescent protein allows us to see different locations of APOE inside living cells.”


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

The first group fed astrocytes oleic acid, an omega-9 fatty acid produced naturally in the body. Using a microscope, the team observed the normal formation of lipid droplets. APOE4, surprisingly, zips into lipid droplets like a magnet and changes the size and shape of the droplets.

It has become abundantly clear to researchers that APOE4 can evade secretion, lock itself inside astrocytes, and translocate into lipid droplets within astrocytes. Windham and Cohen hypothesize that the altered composition of lipid droplets may cause astrocyte dysfunction and affect the ability of microglia to clear amyloid beta.

Lipids: the next frontier

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

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

Source:

Journal Reference:

Windham, IA, etc (2024) APOE traffics in astrocyte lipid droplets and modulates triglyceride saturation and droplet size. Journal of Cell Biology. doi.org/10.1083/jcb.202305003.



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