Loss of the protective protein NRF2 in myelin-producing cells caused changes in mice associated with faster cognitive decline in humans

Loss of the protective protein NRF2 in myelin-producing cells caused changes in mice associated with faster cognitive decline in humans

On August 25, Nature Medicine published a study that compared years of cognitive assessments with postmortem samples of cerebral white matter, which contains many myelinated nerve fibers. People with faster cognitive decline showed changes in myelin, large nerve fibers, and oligodendrocytes. Disabling NRF2 in these cells produced similar changes in mice.

Participants in a British longitudinal study took an IQ test at age 11. From ages 70 to 82, researchers assessed their memory, processing speed, and visuospatial ability approximately every three years. After the participants died, the researchers examined the corpus callosum, a large bundle of nerve fibers connecting the cerebral hemispheres, and compared its tissue features with each person’s rate of cognitive change in later life.

Myelin was less compact in tissue from people with faster cognitive decline. Myelin surrounds nerve fibers, helps them transmit signals, and is produced by oligodendrocytes. Among large myelinated fibers, the axons were thinner, while their sheaths were thicker relative to axon diameter. The same samples contained more oligodendrocytes but a smaller proportion of cells expressing NRF2, a protein that activates cellular protective responses.

The authors tested whether the loss of NRF2 in myelin-producing cells could itself produce this pattern. When the mice were six months old, the researchers disabled the gene encoding NRF2 only in mature oligodendrocytes. By 12 months, modified male mice increased the proportion of time spent in the target sector by 27.82% relative to the first day during four days of a water maze task, in which each animal used a visual cue to locate a hidden platform. Control males showed an increase of 57.75%.

In a separate group of 18-month-old mice with the same gene disabled, the corpus callosum contained thinner myelinated axons and myelin sheaths that were thicker relative to the axons. In humans, this cellular pattern was associated with the rate of age-related cognitive decline. In mice, disabling NRF2 in oligodendrocytes caused similar white matter changes and a smaller improvement in maze performance.