Alzheimer’s risk gene may disrupt brain health
Sarah Cohen’s lab is studying the impact of the APOE4 protein on brain cells in its search for treatments.
A discovery by a UNC School of Medicine cell biology lab could reshape how scientists understand and treat Alzheimer’s disease.
The research team is led by Sarah Cohen, assistant professor in the medical school’s cell biology and physiology department and member of the UNC Lineberger Comprehensive Cancer Center.
Cohen’s lab found that Apolipoprotein E4, a protein long known as the strongest genetic risk factor for late-onset Alzheimer’s, has a surprising effect on certain brain cells.
APOE4 usually works outside the cell, transporting lipids between neurons and support cells. But it can also stick to tiny oil-filled structures called lipid droplets and disrupt the work of astrocytes, star-shaped cells that nourish the brain’s neurons and help maintain brain health.
“It’s causing accumulation of polyunsaturated fatty acids inside lipid droplets,” Cohen said, referring to the types of fats found in foods like fish oil. “We think APOE4 makes the astrocytes more sensitive to stress.”
This effect could explain why APOE4 increases the risk of Alzheimer’s. Understanding whether APOE4 is doing damage inside or outside the cell could be crucial for future drug design. Some companies are trying to develop treatments that reduce APOE levels. “If you have the APOE4 variant, where it’s acting and where it’s bad matters for choosing strategies to get rid of it,” Cohen said.
The work by Cohen’s lab brings new attention to the role of fat metabolism in the brain — an area historically overshadowed by other, higher profile markers of Alzheimer’s. “Lipid accumulation is one of the three hallmarks of the disease, but it’s gotten a lot less attention.”
The lab has mostly researched lipid droplets. With the additional research direction of APOE, the researchers hope to help with finding treatments for neurodegenerative diseases.
Cohen’s interest in APOE’s connections to lipids started when she noticed a University of California, Berkeley, lab study that analyzed all the proteins on the surface of lipid droplets. “APOE came up as a candidate protein,” she said. “That was really intriguing because there was no previous literature about APOE on lipid droplets.”
Read about how Cohen and other researchers developed new ways to see organelles in action.
Initially, Cohen’s team tried to validate APOE’s presence on lipid droplets in liver cells — with no success. But when they turned to astrocytes, where APOE is most abundantly produced in the brain, the protein clearly attached to the lipid droplets. Cohen’s latest study, based on experiments with cultured cells, extends into mouse models of Alzheimer’s in collaboration with Lance Johnson’s lab at the University of Kentucky.
Though the research is in the early stage, its therapeutic implications could be far-reaching. Most Alzheimer’s treatments — including recently approved antibody drugs — target extracellular features like amyloid plaques. These drugs may delay symptoms by several months, but they don’t significantly slow disease progression.
“It’s clear that this treatment alone is not good enough for what patients need,” Cohen said, pointing to the need for new strategies.
Cohen’s lab continues to explore the fundamental biology behind these processes, hoping that the insights might one day refine or even revolutionize treatments for Alzheimer’s disease. “We’re trying to understand what the proteins encoded by these genes normally do, and then what goes wrong when you have a mutation that’s associated with neurodegenerative disease.”
As Cohen’s work reveals, the path to understanding Alzheimer’s may lie in the overlooked fats accumulating inside the brain’s own support cells.
