An international research team led by scientists at the University of Portsmouth says it has identified that one of the major factors of age-related brain deterioration is the loss of myelin. They published their study “Functional genomic analyses highlight a shift in Gpr17-regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum” in Aging Cell.
The loss of myelin results in cognitive decline and is central to several neurodegenerative diseases, such as Multiple Sclerosis and Alzheimer’s disease. This new study found that the cells that drive myelin repair become less efficient as we age and identified a key gene that is most affected by aging, which reduces the cells’ ability to replace lost myelin.
“Brain aging is characterized 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 aging as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS),” write the investigators.
“However, an incomplete understanding of the cellular and molecular processes underlying brain aging 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 aging mouse cerebrum. This was underscored by the identification of causal links between signaling pathways and their downstream transcriptional networks that define oligodendroglial disruption in aging.
“The results highlighted that the G-protein coupled receptor Gpr17 is central to the disruption of OPCs in aging 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.”
The team included Arthur Butt, PhD, director of the Institute of Biomedical and Biomolecular Sciences at the University of Portsmouth with Kasum Azim, PhD, senior research associate at the University of Dusseldorf in Germany. The Italian research groups were led by Maria Pia Abbracchio, professor of pharmacology at the University of Milan and Andrea Rivera, PhD, research fellow at the University of Padua.
“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,” says Butt. “A key feature of the aging 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 [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 aging brain.”
“By comparing the genome of a young mouse brain to that of a senile mouse, we identified which processes are affected by aging,” adds Rivera, who performed the key experiments published in the study. “These very sophisticated analysis allowed us to unravel the reasons why the replenishment of oligodendrocytes and the myelin they produce is reduced in the aging brain.
“We identified GPR17, the gene associated to these specific precursors, as the most affected gene in the aging brain and that the loss of GPR17 is associated to a reduced ability of these precursors to actively work to replace the lost myelin.”
The work is still very much ongoing and has paved the way for new studies on how to induce the “rejuvenation” of oligodendrocyte precursor cells to efficiently replenish lost white matter, according to Azim, who points out that “This approach is promising for targeting myelin loss in the aging brain and demyelination diseases, including Multiple Sclerosis, Alzheimer’s disease and neuropsychiatric disorders. Indeed, we have only touched the tip of the iceberg and future investigation from our research groups aim to bring our findings into human translational settings.”
“MS can be relentless and painful, and there are sadly still no treatments to stop disability progression,” notes Emma Gray, PhD, assistant director of research at the MS Society. “We can see a future where no one has to worry about MS getting worse but, for that to happen, we need to find ways to repair damaged myelin. This research sheds light on why cells that drive myelin repair become less efficient as we age, and we’re really proud to have helped fund it.
“By improving our understanding of aging brain stem cells, it gives us a new target to help slow the progression of MS, and could have important implications for future treatment.”
