Glial cell responses, complement and clusterin expression after lesions in central or peripheral nervous system

Abstract: The present Thesis examines the expression and role of complement and the complement regulator clusterin after central or peripheral axon injury in relation to the responses of non-neuronal cells. Following peripheral sensory nerve injury, complement was expressed in the spinal cord and brain stem in association with reactive microglia, which also appeared to be a local source of complement. Immunoelectron microscopy showed binding of IgG to reactive microglia, as well as to some axotomized neurons. Complement C9 immunoreactivity was present in microglial cells and also in nerve cell membranes.Mice lacking complement C5 (C5(-)) reacted to axon injury with delayed macrophage recruitment as well as axonal and myelin sheath elimination, but normal rate of motor function recovery. Central glia responded in the same way as in control mice, and survival of axotomized motoneurons was unaffected by C5 deficiency.No complement expression was observed along degenerating nerve fibers in the spinal cord, despite the presence of numerous phagocytic microglia. Nor was there any complement expression or glial cell response in the axotomized red nucleus, demonstrating a principal difference to axotomy between peripherally projecting and intrinsic central neurons.Clusterin expression was increased in neurons and perineuronal astrocytes in the red nucleus after rubrospinal tract lesion. Clusterin was also upregulated in astrocytes in central termination areas after sciatic nerve or dorsal root transection. Large, heavily clusterin expressing axonal profiles were observed early and transiently at the site of spinal cord trauma. At a later stage, oligodendrocytes along the degenerating central pathways showed a marked upregulation of clusterin.These findings suggest that i) the continuity between the ganglion cell body and its central process iscrucial for axotomy-induced complement activation, ii) the absence of complement activation after rhizotomy may contribute to the slow removal of degenerating myelin, and iii) complement C5 and/or itsderivatives play a crucial role in macrophage recruitment and nerve fiber elimination, but does not influence functional restoration, axotomy-induced nerve cell death, or central glial responses. The pattern of clusterin upregulation suggests that it is involved in the repair processes following neurotrauma.