Older oligodendrocytes live longer despite damage

IIf neurons are wires, myelin is the insulation that envelops them. Without myelin, electrical leakage occurs and the circuit weakens. This is analogous to what happens in demyelinating diseases such as multiple sclerosis, and to some extent to the cognitive decline that occurs with aging.¹

Oligodendrocytes produce the brain's protective myelin sheaths. When this neuronal insulation is damaged by disease or injury, oligodendrocytes act as a repair team. However, as we age, their ability to produce new oligodendrocyte precursor cells (OPCs) is reduced, making them less effective at repairing damaged myelin.^2.3 However, scientists know little about the lifespan of oligodendrocytes or how they die.

In a study conducted in The Journal of Neuroscience, Researchers followed the aging process of oligodendrocytes and found that mature oligodendrocytes survived DNA damage longer and underwent different cell death compared to younger cells.⁴ A new understanding of the life cycle of oligodendrocytes may provide a starting point for repairing damaged myelin.

“Although we've been studying this topic for decades, we still don't know how these cells die,” said Jason Plemel, a neuroscientist at the University of Alberta who was not involved in the study. To learn more about the life of oligodendrocytes, Robert Hill, a neurobiologist at Dartmouth College and co-author of the study, turned his attention to cell death. Although Hill and his team have been studying the cell biology of oligodendrocytes for some time, they had not yet examined death at the single-cell level, which led them to this study.

To induce cell death in mouse cortical oligodendrocytes and OPCs, the researchers used both cuprizone treatment, an established method to induce demyelination, and a novel technique called two-photon apoptosis target ablation (2Phatal), which they targeted to oligodendrocytes.⁵ Using 2Phatal, they tracked and visualized cell death over a period of 45 days – until now, no one had tracked cell death in living brain tissue over such a long period of time.

Regardless of the treatment used, the researchers observed age-related effects on the type of cell death: newly differentiated oligodendrocytes underwent classic caspase-3-dependent apoptosis, while mature oligodendrocytes died by a caspase-independent process. Most previous studies have only investigated apoptosis as a cell death mechanism in oligodendrocytes.

“[This] is really cool and turns everything we thought on its head, this [mature] cells died,” Plemel said. “When you study how mature oligodendrocytes die, you don't seem to have the right tools to look for it.”

Likewise, the age of a cell influenced its survival. After treatment with 2Phatal or cuprizone, mature oligodendrocytes took longer to die than OPCs—45 days versus one day—and oligodendrocytes undergoing differentiation died at an intermediate time.

“We can't find any other examples of this type of cell death in the brain or the whole body,” Hill said.

It is not yet clear why oligodendrocytes undergo such different cell death processes depending on their age, or why the older cells die more slowly. “It could be that the mature oligodendrocytes lose the machinery required for classic programmed cell death,” Hill said. “Another possibility is that these [mature] The cells are metabolically inactive and do not exchange substances as frequently. Perhaps this is why they survive the catastrophic DNA damage caused by 2Phatal.”

Although research into the role of oligodendrocytes in demyelinating diseases still has much to explore, a better understanding of what causes these cells to die could lead to better treatments that can prevent both types of cell death, preserving the old oligodendrocytes while allowing new oligodendrocytes to grow.