Presence of damaged myelin may be more harmful than its loss: Study

The presence of damaged myelin — the fatty, protective substance surrounding nerve cells that’s lost in multiple sclerosis (MS) — may be more harmful to nerve cells than its removal altogether, according to new preclinical research.

In mouse models of myelin-associated disease, a failure of microglia — the brain’s resident immune cells — to clear away damaged myelin made nerve cell projections more likely to degenerate than when myelin was effectively cleared away. Such degeneration typically occurs in response to inflammatory attacks.

“Our data show that while myelination offers many advantages for higher functions of the nervous system, it also poses a risk for neuroinflammation-related axonal damage and degeneration,” the researchers wrote.

“Our findings are of translational relevance for therapy approaches to modulate neuroinflammation in myelin disease,” the team added — meaning that these results may lead to applications that could directly benefit people with MS and other related disorders.

The study, “Microglia-mediated demyelination protects against CD8+ T cell-driven axon degeneration in mice carrying PLP defects,” was published in Nature Communications.

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Myelin, produced in the brain and spinal cord by cells called oligodendrocytes, protects nerve cells (neurons) from damage, provides them with nutrient support, and helps to speed cell-to-cell communication. In MS, however, myelin in the brain and spinal cord is attacked by the immune system and progressively lost.

The longstanding belief has been that this loss of myelin, or demyelination, directly drives degeneration of nerve cell projections, known as axons, by leaving them vulnerable to inflammatory damage.

“However, the relationship between immune reactions, demyelination, axon degeneration, and clinical disease is unclear, and many observations indicate that loss of myelin itself does not correlate well with progressive neurodegeneration,” the study’s researchers wrote.

Previous research from the study group, comprised of scientists from across Europe, indicated that immune T-cell-mediated attacks may contribute to axon damage in mouse models genetically predisposed to have abnormal or damaged myelin.

Specifically, in mice engineered to produce too much of a myelin protein called proteolipid protein (PLP) — or to have a mutated version of it — T-cells were found to accumulate in myelinated tissue and attack it. But the mechanisms leading to myelin damage were distinct in each model.

While these mouse models are not specifically models of multiple sclerosis, they can still offer insights into MS disease mechanisms, according to the researchers. Indeed, PLP is one of the molecules thought to be targeted by the immune system in MS.

“These models of rare monogenetic diseases offer unique opportunities to reveal mechanisms that have broad relevance for much more frequent disorders,” Rudolf Martini, PhD, professor at the University of Würzburg, in Germany, and the study’s senior author, said in a university press release.

In this research, the scientists returned to these mouse models to further investigate the relationship between the immune system, myelin, and neurodegeneration.

Comparing them, they observed an unexpected inverse relationship between demyelination and axonal loss. While the extent of T-cell driven damage to myelinated axons was similar in both models, the mutated model had a smaller number of non-myelinated nerve fibers but the greatest axon degeneration and functional declines.

Importantly, according to the researchers, small axonal spheroids, or bubble-like structures that form on dying axons, were observed early in both mouse models. These structures were more likely to continue growing — an indicator of progressing neurodegeneration — in the mutated model, where most axons remained myelinated over time.

Taken together, that suggests that nerves with damaged myelin after a T-cell attack were more likely to continue degenerating than cells where the myelin had been removed, in which the damage stopped progressing at an earlier stage.

“This inverse relationship was unexpected and prompted us to study the interactions of abnormal oligodendrocytes and another immune cell type called microglia in more detail,” explained Janos Groh, PhD, a researcher at University of Würzburg and the study’s first author.

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Microglia are resident immune cells in the brain. One important role they play is in a process called phagocytosis, wherein cellular debris from old, damaged, or dying cells — including myelin debris — are engulfed and cleared away.

In a series of experiments, it became apparent that neurodegeneration was slowed when microglia were able to effectively clear away damaged myelin, while nerve cell damage continued to occur when they couldn’t.

“Efficient microglia-mediated removal of perturbed myelin under adaptive immune attack allows the survival of axons at reversible stages of damage,” Groh noted.

Additional data showed, according to Martini, that T-cell attacks caused cellular alterations that resulted in oligodendrocytes winding too tightly around nerve cells.

That resulted in them essentially strangulating the nerve cells “like a constrictor snake,” Martini said.

Taken together, the scientists proposed a model wherein T-cells are prone to attacking myelin segments where oligodendrocytes are perturbed, inducing alterations that cause them to abnormally constrict and damage axons. When microglia are able to clear away the disturbed myelin, it removes the immune system’s target and prevents those cellular alterations, enabling the cells to be preserved.

The findings offer new insights for therapeutic development for demyelinating diseases such as MS. Effective clearance of so-called bad myelin could allow for nerve cells to be covered in a new, healthy, myelin layer — a process called remyelination — before the cells die off altogether. Indeed, efficient remyelination is linked to slowed disease progression in MS.

“Greater insights are needed to identify strategies to block detrimental but still allow or even foster beneficial neural-immune interactions to confer resilience and possibly enable recovery of the perturbed white matter [myelin-coated tissue],” the researchers concluded.