December 13, 2018, New York—More than half of cancer survivors suffer from cognitive impairment from chemotherapy that lingers long after the cancer is gone. In a new study examining the cellular mechanisms behind this condition, scientists led by Michelle Monje of Ludwig Stanford and the Stanford University School of Medicine show that the chemotherapy methotrexate causes a complex set of problems in three major cell types of the brain’s white matter. Published online Dec. 6 in Cell, the study also identifies a potential remedy: A drug now in clinical trials for other indications reversed symptoms of “chemo brain,” as the condition is known, in a mouse model.
In addition to neurons, which transmit nerve impulses, the brain’s white matter contains cells that help neurons function. The research focused on three types of those cells: oligodendrocytes, which produce and maintain myelin, the fatty insulating sheath around nerve fibers; astrocytes, which link neurons to their blood supply, promote proper connections between neurons and maintain the neurons’ environment; and microglia, immune cells that can engulf and destroy foreign invaders in the brain and sculpt neural circuitry.
Comparing postmortem frontal lobe brain tissue from children who had and had not received chemotherapy, the researchers showed that there were far fewer oligodendrocyte lineage cells in the brains of the chemotherapy-treated children. To figure out what was happening to these cells, the researchers injected young mice with methotrexate at levels designed to replicate human exposures and then compared their brains to untreated mice.
Methotrexate, they found, damaged the brain’s populations of oligodendrocyte precursor cells. Normally, these cells can quickly divide to replace any that are lost, but after methotrexate was administered, this self-renewal did not happen correctly. The same problem was seen in mouse brains six months after methotrexate was administered. Transmission electron microscopy revealed deficiencies in the myelin insulation around nerve fibers that resembled changes in the brains of humans who have received chemotherapy. Behavioral problems in the mice also resembled those of humans with chemo brain, including motor impairment, anxiety, and impaired attention and short-term memory.
Further study showed that changes in the brain’s environment were causing oligodendrocyte dysfunction. The researchers found that microglia, the brain’s immune cells, were persistently activated for at least six months after methotrexate exposure. This, in turn, caused problems for astrocytes. Administering a drug that selectively depleted microglia to mice treated with methotrexate reversed many of the cognitive symptoms of chemo brain and reversed the abnormalities in oligodendrocyte maturation, activation of astrocytes and myelin thickness.
“If we understand the cellular and molecular mechanisms that contribute to cognitive dysfunction after cancer therapy, that will help us develop strategies for effective treatment,” Monje said. “It’s an exciting moment.”
The press release from which this summary is derived can be found here.
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Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit www.ludwigcancerresearch.org.
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