Mouse Study Finds Potential Treatment for Myelin Repair for MS, Aging

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by Steve Bryson PhD |

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myelin, GPR17 gene activity

A decline in the activity of the GPR17 gene is responsible for age-related brain deterioration caused by the loss of myelin, a fatty substance that surrounds nerve cells like a sheath, a mouse study discovered.

Researchers identified a small molecule that rejuvenated older cells responsible for generating new myelin, which reversed age-related myelin loss.

This compound may have therapeutic potential for restoring myelin in people with multiple sclerosis (MS). 

The 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,” was published in the journal Aging Cell

The myelin sheath, a fatty coat surrounding nerve fibers (axons), allows electrical impulses to transmit quickly and efficiently between nerve cells. Axons wrapped in myelin give the white matter in the brain its lighter appearance. 

“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,” Arthur Butt, PhD, a professor at the University of Portsmouth, in the U.K., and the study’s lead author, said in a press release

In the brain, myelin is generated by cells called oligodendrocytes, which are regularly replaced by precursor cells known as oligodendrocyte progenitor cells (OPCs).

Increasing evidence suggests a loss of myelin is an essential factor contributing to age-related cognitive decline. Although the underlying mechanism of myelin loss in aging remains unresolved, studies suggest the decline in OPC regeneration is a primary factor.

This decline also is believed to underlie several neurodegenerative diseases, such as Alzheimer’s disease and MS, and studying it in aging animals may contribute to a better understanding of myelin loss in these conditions. However, the molecular processes that govern OPC decline are unknown. 

“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,” Butt said.

“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,” he said.

Now, Butt and colleagues at the University of Portsmouth, also in the U.K., in collaboration with scientists in Germany and Italy, compared the gene activity and active signaling pathways in the brains of 1-month-old and 18-month mice. Their goal was to understand the molecular differences that contribute to age-related myelin decline.

“By comparing the genome of a young mouse brain to that of a senile mouse, we identified which processes are affected by aging,” said Andrea Rivera, PhD, the study’s first author.

This “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,” Rivera said.

The analysis revealed that oligodendrocyte genes are the most significantly altered genes in the brain during aging. Specifically, the team identified a gene called Gpr17 that was exclusively active in a subset of rapidly growing oligodendroglial cells that occur at an intermediate stage between OPCs and fully mature myelinating oligodendrocytes. 

Other genes most altered in aging were myelin-related — specifically Mog, Plp1, Cnp, and Ugt8a — and genes coding for the myelin proteins Cldn11 and Tspan2. A gene involved in protein recruitment for myelin, called Mal, also was among the most altered. 

These analyses “signify oligodendroglial genes as highly susceptible to age‐related changes in the mouse cortext [brain],” the team wrote. 

Further analysis confirmed the most altered processes in aged myelinating oligodendrocytes were associated with myelination. At the core was the Egfr gene (epidermal growth factor receptor), vital in oligodendrocyte regeneration and myelin repair. 

In aged OPCs, the most prominent aging changes were related to nerve cell development, regulation of cell signaling, and organization of the extracellular matrix — a network of proteins that provides support to surrounding cells. Moreover, age-induced OPC gene networks demonstrated Gpr17 as a major regulator, central to many pro‐oligodendroglial mechanisms. 

These results placed “Gpr17 at the core of these OPC signalling networks that are most altered in the ageing brain,” the team added. 

The team then investigated how aging OPC regulatory networks translated into cellular changes by examining various stages in which OPCs become mature myelinating oligodendrocytes. Experiments confirmed Gpr17 activity is significantly and markedly decreased in aging cells as compared with younger cells. 

“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,” Rivera said.

Next, a computer analysis identified LY294002, a small molecule compound with the potential to rejuvenate aged OPCs. The team tested the effects of LY294002 in an aged mouse model infused with a demyelinating agent. 

Demyelination was confirmed 14 days after infusion, together with a decrease in the overall number of OPCs and myelinating oligodendrocytes, compared with controls. LY294002 treatment reduced demyelination and increased the numbers of OPCs and myelinating oligodendrocytes. 

Furthermore, LY294002 showed pro-oligodendroglial and anti-inflammatory effects compared with untreated controls. 

“This approach is promising for targeting myelin loss in the aging brain and demyelination diseases, including multiple sclerosis, Alzheimer’s disease, and neuropsychiatric disorders,” said Kasum Azim, PhD, at the University of Dusseldorf, in Germany, a study co-lead author.

“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.”

This analysis “identified oligodendroglial genes amongst the most altered in the aged mouse [brain], highlighting Gpr17 as a major factor in the disruption of the regenerative capacity of OPCs and decline in myelination,” the investigators concluded. 

The MS Society in the U.K. partially funded the study.

“MS can be relentless and painful, and there are sadly still no treatments to stop disability progression,” said Emma Gray, PhD, of the charity organization.

“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,” Gray said.

“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,” she added. 

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