Axon damage and repair in multiple sclerosis

It is well known that within long-standing multiple sclerosis (MS) lesions there is axonal loss but whether it is an early or late event has been more difficult to establish. The use of immunocytochemical methods that reveal axonal end-bulbs is a valuable approach to investigating acute axonal injur y in human pathological material. The application of these techniques to mu ltiple sclerosis tissue reveals evidence of axonal injury in acute lesions; the distribution of the end-bulbs in acute and active-chronic lesions is a ssociated with regions of maximal density of infiltrating macrophages. Axon injury within the MS lesion will result in both Wallerian degeneration of the axon and also retrograde degeneration of the cell body. The functional consequences of the axon injury will depend upon numbers of axons injured a nd the topographical organization of the fibres coursing through the lesion . The molecular mechanisms by which the recruited leucocytes damage or transe ct the axons are not known. However, investigations in the Wld mutant mouse with very slow Wallerian degeneration demonstrate that axon degeneration i s not simply a passive disintegration of the axon but has clear parallels w ith the active processes of programmed cell death. The presence of early ax on injury and the consequences of an ever increasing load of neuronal damag e has important implications not only for when therapy should be initiated in MS but also the therapeutic target.