Axonal Injury Disrupts Axonal Transport

Disruption of axonal transport is a common response to axonal injury. Thus, the abnormal accumulation of axonally transported proteins along axons can be used to identify axonal damage. Axonal injury in MS has been identified by

Figure 2 Concepts on pathogenesis of neurological disability in patients with multiple sclerosis (MS). Historically, permanent disability occurred when normal myelinated axons (A) underwent immune-mediated demyelination (B) resulting in chronic demyelination and persistent conduction block (C). Restoration of impulse conduction and neurological function may occur as a result of remyelination (D) or redistribution of Na+ channels along chronically demyelinated axonal segments (E). Conceptually, permanent disability is now associated with axonal transection (F) that occurs during inflammatory demyelination (B) and is clinically silent during relapsing-remitting MS because of CNS compensation for axonal loss. Recent evidence suggests that chronic demyelination (C, E) leads to axonal degeneration (G). (Adapted from Trapp et al., 1999a, with permission.)

Figure 2 Concepts on pathogenesis of neurological disability in patients with multiple sclerosis (MS). Historically, permanent disability occurred when normal myelinated axons (A) underwent immune-mediated demyelination (B) resulting in chronic demyelination and persistent conduction block (C). Restoration of impulse conduction and neurological function may occur as a result of remyelination (D) or redistribution of Na+ channels along chronically demyelinated axonal segments (E). Conceptually, permanent disability is now associated with axonal transection (F) that occurs during inflammatory demyelination (B) and is clinically silent during relapsing-remitting MS because of CNS compensation for axonal loss. Recent evidence suggests that chronic demyelination (C, E) leads to axonal degeneration (G). (Adapted from Trapp et al., 1999a, with permission.)

the abnormal accumulation of amyloid precursor proteins (APP) (Gehrmann et al., 1995; Ferguson et al., 1997), non-phosphorylated neurofilament proteins (Trapp et al., 1998), the pore-forming subunit of N-type calcium channels

(Kornek et al., 2001), and metabotropic glutamate receptors (Geurts et al., 2003) along axons in active lesions and at the borders of chronic active lesions. Additional studies have confirmed correlations between inflammatory activity of lesions and APP-positive axons in MS and experimental autoimmune encephalomyelitis (EAE) (Kornek et al., 2000, 2001; Bitsch et al., 2000). The aforementioned studies establish that axonal damage occurs during inflammatory demyelination and correlates with the degree of inflammation in cerebral MS lesions.

While accumulation of axonally transported proteins is a reliable indicator of disrupted axonal transport and therefore axonal injury, the extent and timing to which injured axons either degenerate or functionally recover is unknown. For example, ^-acetyl aspartate (NAA) is used as an in vivo marker of axonal function with decreased levels indicating axonal injury and loss in MS (Bjartmar and Trapp, 2001). However, increased levels of NAA in regions previously identified with reduced NAA indicate that injured axons can survive and axonal injury is reversible (De Stefano et al., 1995). The observations of axonal injury in MS lesions were extended, and the occurrence of permanent axonal damage in the form of transected axons were substantiated for the first time in acute MS lesions by an immunocytochemical study using confocal microscopy (Trapp et al., 1998). Using nonphosphorylated neurofilaments, axonal dilations and axonal ovoids indicative of axonal injury were identified in active and chronic active cerebral MS lesions from patients with disease durations ranging from 2 weeks to 27 years (Fig. 3A, B). Accumulation of axonal proteins and formation of axonal ovoids are highly suggestive of transected axons, as terminal ovoids are formed by the accumulation of proteins by anterograde transport at the proximal ends of transected axons (Fig. 2). However, not all axonal ovoids occur at the terminal ends of transected axons. The formation of en passant axonal ovoids also occurs along damaged axons that remain intact. Whether axons with en passant axonal ovoids degenerate or axonal transport is restored, allowing resumption of normal axonal function, is unknown. Therefore, to accurately determine the extent of axonal transection, quantification of terminal ovoids is required. Further analyses of the nonphosphorylated neurofilament-positive axonal ovoids in MS lesions using three-dimensional reconstruction of

Figure 3 Axonal damage identified in multiple sclerosis lesions by immunostaining for nonphosphorylated neurofilaments (A—D) and visualized by DAB immunohistochemistry (A, B) or immunofluorescence (C, D, green). Demyelinated axons and axonal ovoids suggestive of axonal transection were detected in chronic active (A) and active MS lesions (B). While most axonal ovoids had single axonal connections indicative of axonal transection (C, arrows), some had dual axonal connections (C, arrowhead). Nonphosphorylated-neurofilament-positive axons (D, green) are undergoing active demyelination (arrowheads, red is myelin basic protein). Two axons end in terminal ovoids (arrows). (Panels C and D reproduced from Trapp et al., 1998, with permission.)

Figure 3 Axonal damage identified in multiple sclerosis lesions by immunostaining for nonphosphorylated neurofilaments (A—D) and visualized by DAB immunohistochemistry (A, B) or immunofluorescence (C, D, green). Demyelinated axons and axonal ovoids suggestive of axonal transection were detected in chronic active (A) and active MS lesions (B). While most axonal ovoids had single axonal connections indicative of axonal transection (C, arrows), some had dual axonal connections (C, arrowhead). Nonphosphorylated-neurofilament-positive axons (D, green) are undergoing active demyelination (arrowheads, red is myelin basic protein). Two axons end in terminal ovoids (arrows). (Panels C and D reproduced from Trapp et al., 1998, with permission.)

confocal microscopy images provided conclusive evidence that many of the axonal ovoids contained a single axonal connection and therefore were the proximal ends of transected axons (Fig. 3C). Quantification of terminal ovoids identified a strong correlation between axonal transection and the inflammatory activity of lesions. On average, more than 11,000 terminal ovoids/mm3 were detected in active lesions, more than 3,000/mm3 were identified at the edge of chronic active lesions, and approximately 900/mm3 were detected within the core of chronic active lesions. In contrast, control white matter contained less than 1 transected axon/mm3. The correlation of significant amounts of axonal transection with inflammation in patients with short disease duration when inflammatory demyelination is predominant helped establish the occurrence of axonal loss at disease onset in MS (Fig. 3D).

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