Cellular Axon Components

1. Axon Heterogeneity

The majority of axons in the human CNS are myelinated and the thickness of the myelin sheath is proportional to the diameter of the axon (Hirano and Llena, 1995). Intuitively one might expect that the myelin sheath would act to "protect" the axon from the potentially damaging effects of inflammatory cells and their secretory products. Axons are not uniform along their length, however, and different axon populations may differ in their susceptibility to injury. All myelinated axons of the CNS have nodes of Ranvier where the myelin sheath is absent. The node of Ranvier could be a susceptible site for injury (Fig. 2) in an inflammatory milieu; it appears to be particularly susceptible to injury after axon stretch (Maxwell and Graham, 1997) and also in the peripheral nervous system (PNS) to antibody-mediated injury (Griffin et al., 1996). The thinning of the axon, the lack of the myelin sheath, and the accumulation of mitochondria may all predispose the nodal region to injury. Another region of the axon that might also be important in this regard is the axon terminal region where the axon loses its myelin sheath as it branches to form the profuse ending typical of many axons (Fig. 2). Whether the terminals or their branch points are susceptible regions is not known. The axon hillock is also exposed and may be susceptible to injury in lesions that border or lie within the gray matter. There is evidence that small-caliber axons are more susceptible to injury than large-caliber axons (Medana and Esiri, 2003).

In addition to heterogeneity of axon size and possible focal points of susceptibility, axons have intrinsic differences in that they arise from different neuron populations, each of which has its own molecular phenotype. An example of this heterogeneity is to be found in the different neu-

rotransmitters that axons transport to their terminals. The potential significance of this variable is raised by recent studies investigating the impact of inflammation on neurons of the substantia nigra. A focal innate inflammatory response, induced by the local injection of endotoxin into the normal brain, does not lead to significant neuronal degeneration except when the endotoxin is injected into the substantia nigra (Herrera et al., 2000) when large numbers of the tyrosine hydroxylase containing neurons die. Whether the susceptibility of the dopaminergic cell bodies is reflected in their axonal response to an inflammatory challenge is not known, and whether this susceptibility is to be found in other populations during different forms of inflammation is also unknown.

2. Demyelinated Axons

It is a sine qua non of MS pathology that there are regions of CNS fiber tracts that are demyelinated. It is a matter of considerable importance to discover whether the loss of the myelin sheath makes axons more susceptible to injury, and how large this effect may be since strategies to promote remyelination may turn out to be also axon protective (Franklin, 2002). There have been a number of suggestions that the severity of demyelination and axon degeneration are related. However, it has not yet been demonstrated with any degree of confidence that for a given degree of inflammation, the axon degeneration is more likely in a demyelinated region than in a myelinated region. Whether populations of unmyelinated fibers are more or less susceptible to inflam

Figure 2 Possible sites of axon injury sensors during an immune mediated assault on the CNS by T-cells and macrophages. Axon injury may occur at the nodes of Ranvier, the axon terminal, or the axon hillock. Fine-caliber axons appear to be more susceptible than large-caliber axons to injury. It has been suggested that demyelinated axons may be more susceptible to injury by inflammatory cells.

Figure 2 Possible sites of axon injury sensors during an immune mediated assault on the CNS by T-cells and macrophages. Axon injury may occur at the nodes of Ranvier, the axon terminal, or the axon hillock. Fine-caliber axons appear to be more susceptible than large-caliber axons to injury. It has been suggested that demyelinated axons may be more susceptible to injury by inflammatory cells.

mation-mediated injury has also not been investigated. This is of some importance given that unmyelinated fibers are to be found throughout the CNS including superficial cortical layers where large lesions may occur in MS (Peterson et al., 2001).

Axon injury and degeneration are a consequence of the inflammatory response around the axons, but an alternative view has also prevailed for many years. This view suggests that it is the consequences of demyelination per se that leads to axon degeneration. It is well established that the myelin-forming cells have a profound effect upon the axon, influencing the axon cytoskeleton and distribution of ion channels (Salzer, 1995) (see Chapter 8), and genetic abnormalities of the myelin sheath may lead to axon degeneration. Although it is not immediately clear how loss of myelin from only a relatively small portion of the axon would produce catastrophic degeneration of the whole axon, it is possible that the local signaling interactions are key. It is possible that local loss of the myelin leads to alterations in the cytoskeleton that alter axon transport in subtle ways. These changes in axon homeostasis may eventually lead to axon degeneration or make the axon susceptible to previously relatively benign inflammatory mediators.

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