NRF2 Downregulation in Oligodendrocytes as a Contributing Cause of Cognitive Decline in Mice
Oligodendrocytes resident in the brain are responsible for maintaining the insulating myelin sheaths around axons that are required for the effective transmission of electrical impulses between neurons. Loss of myelin integrity is the cause of a number of debilitating conditions, but also occurs to some degree with aging. It has been an open question as to how large a contribution this makes to age-related cognitive decline. Researchers here provide evidence for age-related changes in oligodendrocyte behavior and myelin structures to be more complicated than the simple concept of reduced remyelination and loss of myelin integrity, and to correlate with meaningful differences in the trajectory of cognitive decline in mice.
The underlying mechanisms driving cognitive decline in aging remain unclear. Learning in humans in youth and adulthood is associated with increased central nervous system (CNS) myelin, the insulating membrane produced by oligodendrocytes that surrounds neuronal axons to facilitate rapid electrical impulse conduction and provide metabolic support. Furthermore, it is now well established that, in mice, learning requires an increase in oligodendrocytes through de novo generation. Cognitive impairment in aged mice and non-human primates is associated with reduced oligodendrocytes and myelin; however, the white matter pathologies driving human cognitive decline remain unclear. Indeed, although magnetic resonance imaging studies associate white matter abnormalities with cognitive decline in aged humans, the underpinning oligodendrocyte and myelin changes are unknown.
Here we uncover a role for oligodendrocytes in explaining the variance of cognitive decline with aging. By investigating neuropathological and transcriptomic changes in human white matter associated with individual rates of cognitive decline in aging, we find that worse cognitive trajectories unexpectedly associate with smaller myelinated axon size, thicker myelin and more oligodendrocytes with downregulation of NRF2. Aged oligodendrocyte-specific NRF2-knockout mice showed attenuated cognitive improvement over time and mirrored the white matter pathology of human cognitive decline in aging. These findings place the oligodendrocyte as a contributor to cognitive decline and highlight the NRF2 pathway as a therapeutic target to preserve cognition in human aging.