An important discovery has been made about Apolipoprotein E (APOE) – the largest genetic risk factor for late-onset Alzheimer’s disease by researchers. Dr. Sarah Cohen and former Cohen lab PhD student Ian Windham of the UNC School of Medicine.
Older adults who have inherited a genetic variant called APOE4 from their parents have two to three times higher risk of developing the late-onset neurodegenerative disease. Understanding how APOE4 affects brain cells could help researchers develop effective therapeutics and combat the mechanisms that cause the heightened risk of the disease.
Cohen and Windham conducted a meticulous five-year study to better understand and visualize the relationship between APOE4, Alzheimer’s disease, and brain lipids.
„We found that brain cells known as astrocytes are more vulnerable to damage and perhaps even become dysfunctional when surrounded by APOE4 in their lipid storage centers,“ said Cohen, a cell biology and physiology assistant professor and the lead author of the paper published in the Journal of Cell Biology. „This mechanism could explain how exactly APOE4 increases Alzheimer’s risk at the cellular level.“
The Role of Lipids in the Brain
Sixty percent of the dry weight of the brain consists of lipids, which play a crucial role in energy storage in cells and the formation of myelin – the substance that surrounds and insulates neurons. Lipids can be found in specialized fat storage compartments known as lipid droplets in astrocytes.
While helpful, lipids can become toxic under the right conditions. When neurons are excited or stressed, they release toxic lipids into the environment. Astrocytes are responsible for cleaning up the freely floating toxic lipids, preventing them from accumulating in the brain.
If astrocytes become damaged or dysfunctional in any way, they may fail to perform their cleansing duties. Consequently, other brain cells called microglia can’t eliminate amyloid beta plaques in the brain, another driving factor for Alzheimer’s disease.
Seeing APOE in Real Time
APOE is produced by astrocytes. Similar to a taxi or Uber, the protein monitors the release and transport of lipids between cell types in the brain. The team wanted to find out exactly what happens to the lipids in astrocytes. Windham led the charge and developed a labeling and tagging system that would allow them to see the inner workings of astrocytes in action under the microscope.
„Labeling APOE with green fluorescent protein allowed us to see the various places APOE reaches in live cells.“
– Ian Windham, now a Postdoctoral Fellow at Rockefeller University and lead author of the paper
The team initially fed the astrocytes with oleic acid, an omega-9 fatty acid naturally produced in the body. Using a microscope, the team observed the typical formation of lipid droplets. Surprisingly, APOE4 migrated like a magnet to the lipid droplets, altering their shape and size.
The researchers became acutely aware that APOE4 can escape secretion, lodge itself in astrocytes, and migrate to lipid droplets within astrocytes. Windham and Cohen suspect that the altered composition of the lipid droplets can cause dysfunction in astrocytes and impair the ability of microglia to eliminate amyloid beta.
Lipids: The Next Frontier
However, more research is needed for details. Cohen hopes that their findings will further highlight the role of lipid droplets in Alzheimer’s disease and other neurodegenerative disorders.
„In Alois Alzheimer’s first work, he described three features of neurodegenerative diseases: amyloid beta plaques, tau tangles, and accumulations of lipids,“ said Cohen. „The first two have received a lot of attention. The next frontier is lipids. As APOE is the largest genetic risk factor, we believe there are clues to how lipids fit into the story.“
University of North Carolina Health Care
Windham, IA, et al. (2024) APOE reaches astrocyte lipid droplets and modulates triglyceride saturation and droplet size. Journal of Cell Biology. doi.org/10.1083/jcb.202305003.