Oligodendrocytes Provide Energy Reserves to Axons
Post by Laura Maile
The takeaway
When the brain is exposed to low glucose and decreased metabolism, as it is in diseases like Alzheimer’s, myelin slowly breaks down. Oligodendrocytes - cells that create myelin - can provide a reserve of energy for the axons of neurons, supporting them through periods of disease or other insults.
What's the science?
Oligodendrocytes are the cells of the central nervous system that create myelin, the fatty substance that surrounds the axons of neurons and helps action potentials propagate down the axon. In addition to creating myelin, oligodendrocytes also support the production of ATP, the energy-associated molecule necessary for many cellular processes. This is important because myelin insulates axons, blocking their access to metabolic molecules in the extracellular space. As we age, myelin must be maintained by the constant turnover and production of new myelin proteins and fatty acids. Fatty acid oxidation is the process that occurs in the mitochondria and peroxisomes where fatty acids are broken down into acetyl-CoA, which can then be used in the production of ATP or of new fatty acids. In disorders associated with loss of myelin such as Alzheimer’s Disease, there is also reduced glucose metabolism in the brain. Scientists don’t yet know whether fatty acid and myelin production are connected to metabolism in oligodendrocytes. This week in Nature Neuroscience, Asadollahi and colleagues studied isolated optic nerves to determine whether axons depend on oligodendrocyte energy metabolism and whether myelin is disrupted when glucose is low.
How did they do it?
The authors studied the optic nerve of young adult mice because of its long, isolated axons. They used transgenic mice bred to express fluorescent proteins in oligodendrocytes. After isolating the optic nerves, they were exposed to different amounts of glucose, and fluorescent staining was used to analyze the total number and identity of surviving and dying cells. Next, they determined whether fatty acid metabolism provides an energy store by starving optic nerves of glucose and exposing them to a drug that blocks fatty acid oxidation in the mitochondria. They also used a high-resolution technique called electron microscopy to examine myelin structure in low glucose environments.
Next, the authors sought to determine whether fatty acid metabolism in oligodendrocytes is important for axon function. They electrically stimulated isolated optic nerves while measuring the size of the evoked action potentials. By increasing the frequency of stimulation, they could observe enhanced firing frequency of axons and measure the area of the resulting action potentials. They next disrupted fatty acid oxidation specifically in the peroxisomes of oligodendrocytes through a genetic mouse model that knocked out a specific gene. Using the same electrical stimulation experiment, they measured the action potential area of stimulated axons that were starved of glucose. Finally, to determine the role of oligodendrocytes in long-term glucose deprivation, the authors generated transgenic mice with an inducible knockout of the GLUT1 glucose transporter in oligodendrocytes. Using this model, they could disrupt glucose availability in oligodendrocytes in adult mice and then observe behavior and myelin structure using electron microscopy.
What did they find?
The authors found that after 24 hours of low glucose exposure, oligodendrocytes and other glial cells suffered little to no cell death in the optic nerve, meaning they had access to some additional energy store. When the optic nerve was exposed to an environment with no glucose and an inhibitor of fatty acid metabolism, 70% of cells died. After 24 hours of low glucose exposure, cells showed signs of cell death and loss of myelin integrity. When optic nerves were deprived of glucose and then electrically stimulated in the presence of a fatty acid oxidation blocker, their evoked action potentials decayed quicker than controls that had normal fatty acid oxidation. This shows that in low glucose environments, axonal function is supported by fatty acid metabolism. In transgenic mice that had a genetic block of fatty acid oxidation in oligodendrocyte peroxisomes, a similar decay in action potential area was observed, indicating that axonal function is supported specifically by oligodendrocytes. Finally, in mice that lacked the GLUT1 glucose transporter in oligodendrocytes, the authors observed loss of myelin even in the absence of behavioral deficits. This suggests that when glucose uptake by oligodendrocytes is low, normal myelin metabolism continues.
What's the impact?
This study found that when neurons are exposed to low glucose, myelin loss, and oligodendrocyte fatty acid breakdown continues, providing support to axons and possibly avoiding permanent axon degeneration. This suggests that oligodendrocytes are important for providing energy reserves for neuronal axons and additionally, that in diseases associated with axonal degeneration and in normal aging, the imbalance between myelin production and degradation may be responsible for progressive loss of myelin.