Wallerian Degeneration

After transection of an axon in the CNS, the cut ends rapidly seal and the distal axon may survive for several days before it begins to undergo wallerian degeneration, the larger axons degenerating before finer caliber axons. After the axon has degenerated, the myelin sheath begins to degenerate; but in marked contrast to the rapid removal of axon and myelin debris from the PNS, the debris in the CNS is slowly cleared over a period of months (Bignami and Eng, 1973). In the human brain and spinal cord, the debris in fiber tracts undergoing wallerian degeneration may persist for years, as it is very slowly removed by mononuclear phagocytes (Miklossy and Van der Loos, 1991; Buss et al., 2004). For reasons that are not well understood, the myelin sheath may persist in a remarkably intact state despite the loss of the axon (Fig. 4).

Wallerian degeneration in the CNS results in the activation of the microglia along the degenerating tract (Fig. 5) (Lawson et al., 1994). These activated microglia are largely composed of proliferating resident microglia, although some monocytes may be recruited at later stages. Activated microglia have been demonstrated in so-called NAWM of the MS brain, in both postmortem material (Allen et al., 2001) and in vivo (Banati et al., 2000). Activated microglia are often attributed with a pro-inflammatory phenotype synthesizing inflammatory cytokines, such as interleukin-1p and tumor necrosis factor-a, but it is now clear that morphological activation of microglia is not synonymous with pro-inflammatory cytokine production (Perry et al., 2002). Indeed the profile of cytokines, or other inflammatory mediators, secreted by a phagocytic macrophage critically depends on the nature of the phagocytosed material and the receptor repertoire used by the macrophage to ingest the debris. It has been shown that macrophages that have ingested apoptotic cells have an anti-inflammatory profile (Henson et al., 2001). A key receptor involved in the generation of this anti-inflammatory profile is the phos-phatidylserine receptor that recognizes phosphatidylserine residues expressed on the external leaflet of the plasma membrane of apoptotic cells. Given the evidence that axons degenerate by an active programmed-cell-death-like process

Figure 4 Preservation of CNS myelin during wallerian degeneration in the spinal cord, although some of the axons have degenerated 3 days previously (x 3000).

and that neuntes undergoing wallerian degeneration in vitro express phosphatidylserine residues on the external axolemma (Sievers et al., 2003), it is of interest to study the cytokine profile associated with the activation of microglia in CNS wallerian degeneration. In contrast to that found in peripheral nerves undergoing wallerian degeneration, it has been found that wallerian degeneration of optic nerve is associated with inflammatory profile with increased expression of transforming growth factor-pi (TGF-pi) and cyclo-oxygenase-2 consistent with their having phagocytosed apoptotic cells or cellular material undergoing an apoptotic-like process (Palin, Cunningham, Perry, unpublished). These activated microglia, however, are "primed" and after a systemic challenge with endotoxin, to mimic a systemic infection, the cytokine profile is switched to the expression of significant levels of pro-inflammatory cytokines. A recent microarray analysis of white matter taken from distal to plaques in MS postmortem material also failed to find a typical pro-inflammatory profile despite the large numbers of activated microglia present (Graumann et al., 2003). These authors found upregulation of genes involved in pathways related to the response to oxidative stress and ischemic preconditioning.

The presence of activated microglia distal to plaques may have two obvious consequences. First, it has been shown in experimental models of EAE that degenerating fiber tracts and the presence of activated microglia may act as a target for the entry of activated T-cells and the initiation of an inflammatory lesion (Konno et al., 1990). The mechanisms underlying the targeting of inflammation to the degenerating fiber tracts are not known, and it is unclear to what extent this also happens in the human CNS. Second, the phagocytosis of material from degenerating axons and myelin may act to prime the microglia so that a secondary stimulus, such as that evoked by a systemic infection, may further activate the microglia (Perry et al., 2003). A significant proportion of clinical relapses are triggered by systemic infections (Buljevac et al., 2002).

Wallerian Degeneration Optic Nerve
Figure 5 Activated microglia in the murine optic nerve undergoing wallerian degeneration 28 days postinjury. The activated microglia as revealed by CD68 (A) are readily visible, whereas those in the normal optic nerve (B) are fewer, and express low levels of CD68. Scale bar = 80 |m.

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