Today's research materials report on an investigation of the age-related loss of myelin in the nervous system. The insulating sheath that surrounds nerves is made up of myelin. Its presence ensures the proper conduction of nerve impulses along the axons that connect neurons in the nervous system. The structure and maintenance of myelin sheathing has been most studied in the context of demyelinating conditions such as multiple sclerosis, in which the immune system causes a breakdown of myelin. This leads to increasingly severe symptoms as the nervous system loses its ability to function.
Loss of myelin sheathing integrity occurs not just in demyelinating conditions, however, but also in aging. There is compelling evidence for myelin degradation in old age to be a significant contribution to cognitive decline, for example. Here the problem appears to be a matter of diminished activity in the oligodendrocyte cell population responsible for maintaining myelin. There are numerous possible contributing causes: loss of stem cell function; cellular senescence; chronic inflammation; and many more. It remains unclear as to which of these mechanisms are more or less important. Regardless, therapies capable of restoring myelin, hopefully an outcome of ongoing work on demyelinating conditions, could be of great interest to older people as well.
"Everyone is familiar with the brain's grey matter, but very few know about the white matter, which comprises of the insulated electrical wires that connect all the different parts of our brains. A key feature of the ageing brain is the progressive loss of white matter and myelin, but the reasons behind these processes are largely unknown. The brain cells that produce myelin - called oligodendrocytes - need to be replaced throughout life by stem cells called oligodendrocyte precursors. If this fails, then there is a loss of myelin and white matter, resulting in devastating effects on brain function and cognitive decline. An exciting new finding of our study is that we have uncovered one of the reasons that this process is slowed down in the ageing brain."
"By comparing the genome of a young mouse brain to that of a senile mouse, we identified which processes are affected by ageing. These very sophisticated analysis allowed us to unravel the reasons why the replenishment of oligodendrocytes and the myelin they produce is reduced in the ageing brain. We identified GPR17, the gene associated to these specific precursors, as the most affected gene in the ageing brain and that the loss of GPR17 is associated to a reduced ability of these precursors to actively work to replace the lost myelin."
Brain ageing is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age-related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to ageing as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain ageing hinders the development of regenerative strategies.
Here, our combined systems biology and neurobiological approach demonstrate that oligodendroglial and myelin genes are amongst the most altered in the ageing mouse cerebrum. This was underscored by the identification of causal links between signalling pathways and their downstream transcriptional networks that define oligodendroglial disruption in ageing. The results highlighted that the G-protein coupled receptor Gpr17 is central to the disruption of OPCs in ageing and this was confirmed by genetic fate-mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPCs and restore myelination in age-related neuropathological contexts.