Axon injury is a significant part of MS pathology. Postmortem analysis shows that axon injury occurs early in the evolution of the plaque, and the degree of axon injury correlates with the intensity of the inflammatory response. Quantitative analysis reveals that a significant percentage of axons degenerate in major fiber tracts. Studies in animal models of MS show that axon injury also occurs in a number of these models. The transection of an axon by inflammatory cells and their products is an irreversible lesion and insights into the early stages of this process are needed.
A spectrum of molecules secreted by inflammatory cells including T-cells, B-cells, and macrophages in an immuno-logically nonspecific manner may precipitate axon transec-tion. These "molecular scissors" may act on the axon in a number of different ways. They may activate biochemical pathways, intrinsic to the axon, that lead to local autodestruction akin to programmed-cell-death, or apoptosis, of the cell body.
The myelin sheath may protect the axon from some of the potentially destructive molecules, but exposed parts of the axon, such as the node of Ranvier and axon terminal, remain sites susceptible to injury. Demyelination may compromise axon homeostasis and axonal transport and thus predispose these axons to injury by inflammatory mediators. Changes in axon transport or other aspects of axon home-ostasis may have subtle effects on synaptic signaling, particularly over a long period of time.
Axon transection in plaques within the fiber tracts leads to wallerian degeneration of the distal axon segment and a retrograde reaction at the cell body. These processes are associated with the activation of microglia distal to the plaque. The possible role of this innate immune response on adjacent intact axons and neuronal function and integrity has not been explored. Comparison of the innate inflammatory response in MS with the innate response in acute brain injury and the consequences of this inflammation may provide useful insights.
Strategies to prevent axon injury by inflammatory cells or demyelination are much needed. Current anti-inflammatory therapies do not appear to affect long-term outcome, suggesting that the mechanisms of axon injury and the innate inflammatory response as a consequence of this axon injury are not being targeted. Therapeutic interventions to target the molecules of destruction that are secreted by inflammatory cells that act as molecular scissors to precipitate axon transection are much needed.
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