The evidence for primary axonal loss in multiple sclerosis

INTRODUCTION: At what stage in the pathogenesis of multiple sclerosis (MS) does the damage to axons occur, and why should there be any axon loss at all in what is thought to be principally an axon sparing demyelinating disease? A recently described new technique for investigating axon damage depends for its ability on the immunoreactivity of amiloid precursor protein (APP), which has been shown to be more sensitive than silver stains for detecting damaged axons. DEVELOPMENT: We used APP immunoreactivity as a method to investigate whether axon damage occurs in acute MS lesions. The results of our APP staining showed that the expression of APP in MS lesions is associated with acute MS lesions and the active border of less acute lesions. There was little, if any, APP expression in the chronic lesions. If we accept that the APP staining represents irreversible damage to some axons, the next question is what factors are responsible for mediating damage to axons in MS? Matrix metalloproteinases (MMP) are expressed by macrophages in acute MS lesions and in the active borders of active chronic lesions. The injection of highly-purified MMP into the brain results in demyelination, blood-brain barrier breakdown, and axonal loss. Moreover, the inhibition of the MMP activity reduces the severity of MS-like lesions in experimental models. Thus the properties and distribution of these enzymes make them rational targets for therapeutic intervention. CONCLUSION: Whatever mechanism proves to be responsible for axonal damage in MS, it is clear that this disease should, perhaps, be more appropriately recognized as a primary demyelinating entity with associated primary axonal loss.