For oligodendrocytes (the central nervous system cells critical to brain function), age may not bring wisdom, but it does bring the power to hold on to life for much, much longer than scientists believed. This is according to a new study featured on the March 27 cover of the magazine Neuroscience Magazine.
Mature oligodendrocytes took 45 days to die after a fatal trauma that killed younger cells within the expected 24 hours, Dartmouth researchers report. The findings suggest that there is a new avenue for efforts to reverse or prevent the damage that aging and diseases such as multiple sclerosis cause to these important cells.
In the brain, oligodendrocytes wrap around the long, thin connections between nerve cells known as axons, where they produce a lipid membrane called myelin sheath that covers the axon. Axons transmit the electrical signals that nerve cells use to communicate; Myelin sheaths, like the plastic coating on a copper wire, help these signals travel more efficiently.
Old age and neurodegenerative diseases such as MS damage oligodendrocytes. When cells die, their myelin production dies with them, causing the myelin sheaths to break down with nothing to replace them. This can lead to loss of motor function, feelings, and memory as neurons lose the ability to communicate.
Scientists have assumed that damaged oligodendrocytes, like all damaged cells, initiate cellular self-destruction called apoptosis in which the cells kill themselves. But Dartmouth researchers found that mature oligodendrocytes can experience a longer lifespan before death than has ever been seen before. The findings raise the critical question of what changes in these cells as they mature allow them to persist.
“We found that mature cells follow a pathway that is still controlled, but not the classic programmed cell death pathway,” said Robert Hill, assistant professor of biological sciences and corresponding author of the paper.
“We think this shows us what happens in the brain as we age and reveals a lot about how these cells die in older people,” Hill said. “That unique mechanism is important for us to investigate further. We need to understand why these cells follow this pathway so we can promote it or prevent it, depending on the context of the disease.”
First author Timothy Chapman, who led the project as a doctoral candidate in Hill’s research group, said efforts to develop treatments to preserve myelin have focused on growing young oligodendrocytes and protecting mature ones. But this study suggests that cells can change significantly as they age and that a single treatment may not work.
“In response to the same thing, young cells go one way and old cells go another,” said Chapman, who is now a postdoctoral researcher at Stanford University. “If you want to protect old cells, you may have to do something completely different than if you wanted to help young cells mature. You’ll probably need a dual approach.”
The paper is based on a living tissue model that the team reported in the journal Nature Neuroscience in March 2023 that allows them to initiate the death of a single oligodendrocyte to observe how surrounding cells react. They reported that when an oligodendrocyte in a young brain died, the cells around it immediately replaced the lost myelin. However, in a brain equivalent to that of a 60-year-old, the surrounding cells did nothing and the myelin was lost.
“That model gets us as close as possible to the cell death process that occurs in the brain,” Hill said. “We can model the effects of aging very well. Our ability to select a single oligodendrocyte, watch it die, and observe how it regenerates or does not regenerate allows us to understand what drives this process at the cellular level and how it can be controlled.”
For the latest study, the researchers used their model to fatally damage the DNA of oligodendrocytes using what amounts to a cell death ray: a photon-based device called 2Phatal that Hill developed. They also used the standard method of removing myelin that uses the copper-based toxin cuprizone as a comparison.
As previous studies reported, the immature cells died quickly. But the older cells survived, which the Dartmouth team initially interpreted as resistance to DNA damage.
The study focused when researchers examined the mature cells 45 days later using a long-term, high-resolution imaging technique developed in Hill’s lab. “That’s when we saw that it wasn’t that the cells were resistant to damage, but that they were experiencing this prolonged cell death,” Hill said.
“No one has ever proven cell death so long after DNA damage. It is the only example we can find in the literature where a cell experiences such a traumatic event and remains for more than a week,” he said.
Because humans have oligodendrocytes for life, the cells are known to accumulate DNA damage and are more resistant than other cells, Chapman said. “That’s why we think this effect applies to aging. One reason these cells can persist for so long is because they are accustomed to experiencing this type of damage naturally during aging,” she said.
The study opens the first door to a vast labyrinth of more questions, Hill and Chapman say, such as whether prolonged death is a good thing. It may be the equivalent of dysfunctional myelin, which is worse simply sitting on an axon than if there was no myelin at all, Hill said. It isolates the cell from the surrounding tissue and essentially deprives it of nutrients.
“It’s almost like there’s junk in the axon for 45 days. Do we want to save that junk or speed up its removal? We didn’t even know that was a question until we saw this,” Hill said.
“If we understand the mechanism of cell death, maybe we can speed it up and get rid of that dysfunctional myelin,” he said. “We’re always trying to save cells and tissue, but you have to know if it’s worth saving.”