Aging compromises oligodendrocyte precursor cell maturation and efficient remyelination in the monkey brain
Christina Dimovasili1, Ashley E Fair2, Isabella R Garza2
1Laboratory for Cognitive Neurobiology, Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, USA. cdimovasili@gmail.com.
Abstract:
Age-associated cognitive decline is common among otherwise healthy elderly people, even in the absence of Alzheimer's disease and neuron loss. Instead, white matter loss and myelin damage are strongly associated with cognitive decline. Myelin is subject to lifelong oxidative stress that damages the myelin sheath, which is repaired by cells of the oligodendrocyte lineage. This process is mediated by oligodendrocyte precursor cells (OPCs) that sense the damage and respond by proliferating locally and migrating to the region, where they differentiate into mature myelinating oligodendrocytes. In aging, extensive myelin damage, in combination with inefficient remyelination, leads to chronically damaged myelin and loss of efficient neuronal conduction. This study used the rhesus monkey model of normal aging to examine how myelin regeneration capacity is affected by age. Results show that older subjects have reduced numbers of new BCAS1 + myelinating oligodendrocytes, which are newly formed cells, and that this reduction is associated with poorer cognitive performance. Interestingly, this does not result from limited proliferation of progenitor OPCs. Instead, the transcription factor NKX2.2, which regulates OPCs differentiation, is significantly decreased in aged OPCs. This suggests that these OPCs have a diminished potential for differentiation into mature oligodendrocytes. In addition, mature oligodendrocytes have reduced RNA expression of two essential myelin protein markers, MBP and PLP. These data collectively suggest that in the normal aging brain, there is a reduction in regenerative OPCs as well as myelin production that impairs the capacity for remyelination.
Insights
Cognitive decline in aging is linked to myelin damage and reduced repair. Older monkeys show fewer new myelin-producing cells and impaired differentiation, hindering brain repair.
Area of Science:
- Neuroscience
- Aging Research
- Cell Biology
Background:
- Age-associated cognitive decline is common in healthy elderly individuals.
- White matter loss and myelin damage correlate with cognitive decline, independent of neuron loss.
- Myelin damage from oxidative stress is repaired by oligodendrocyte precursor cells (OPCs).
Purpose of the Study:
- To investigate how aging affects the brain's capacity for myelin regeneration using a rhesus monkey model.
- To identify age-related changes in oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes.
- To correlate myelin regeneration capacity with cognitive performance in aging.
Main Methods:
- Utilized the rhesus monkey model of normal aging.
- Examined the numbers of new BCAS1+ myelinating oligodendrocytes in aged subjects.
- Assessed the proliferation and differentiation potential of OPCs, focusing on the transcription factor NKX2.2.
- Measured RNA expression of myelin protein markers (MBP and PLP) in mature oligodendrocytes.
Main Results:
- Older rhesus monkeys exhibited reduced numbers of new myelinating oligodendrocytes, associated with poorer cognitive function.
- OPC proliferation was not limited in aged subjects; however, the transcription factor NKX2.2 was significantly decreased.
- Mature oligodendrocytes in aged brains showed reduced expression of myelin proteins MBP and PLP.
- These findings indicate an impaired capacity for remyelination in the aging brain.
Conclusions:
- Aging impairs the brain's ability to regenerate myelin due to reduced differentiation potential of OPCs and decreased myelin production by mature oligodendrocytes.
- The decline in myelin regeneration capacity contributes to age-associated cognitive decline.
- Targeting OPC differentiation and myelin production may offer therapeutic strategies for cognitive aging.
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