[en] Axons undergo Wallerian degeneration distal to a point of injury. Experimental investigations have documented many of the cellular and molecular events that underlie this behaviour. Since relatively little is known about such events in human CNS pathologies and current experimental intervention strategies indicate the possibility of significant axon regeneration along the original degenerated fibre tract, we performed an immunohistochemical investigation of the dynamics of Wallerian degeneration in post mortem spinal cords of patients who died 2 days to 30 years after either cerebral infarction or traumatic spinal cord injury. Neurofilament (NF) staining demonstrated a spatio-temporal pattern of axonal loss within degenerating descending nerve fibre tracts that could be detected close to the lesion as early as 12 days after injury and progressed to an almost complete loss of NF immunoreactivity at survival times of 1 year and longer. Immunohistochemistry for glial fibrillary acidic protein revealed a late astrocytic reaction starting at 4 months after injury in the degenerating tracts, leading to the long-term deposition of a dense astrocytic scar. These events were accompanied by the gradual reduction of myelin basic protein in affected nerve fibre tracts, leading to almost complete loss by 3 years after injury. Since the extracellular matrix molecule chondroitin sulphate proteoglycan (CSPG) is known to be strongly inhibitory for axonal regeneration and to be a major component of gliotic scar tissues, we investigated the possible deposition of CSPG within the degenerating nerve fibre tracts. Apart from a local up-regulation close to the lesion site, our results show no enhanced CSPG expression within degenerated tracts at any survival time. This suggests that despite the apparent lack of CSPG in Wallerian degeneration, the slow reduction of CNS myelin and the long-term deposition of a dense astrocytic scar may present an environment that is non-supportive for axon regrowth.
Disciplines :
Neurology Neurosciences & behavior
Author, co-author :
Buss, A.
Brook, G. A.
Kakulas, B.
Martin, Didier ; Université de Liège - ULiège > Département des sciences cliniques > Neurochirurgie
Franzen, Rachelle ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Neuro-anatomie
Schoenen, Jean ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Neuro-anatomie
Noth, J.
Schmitt, A. B.
Language :
English
Title :
Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord
Becerra JL, Puckett WR, Hiester ED, Quencer RM, Marcillo AE, Post MJ, et al. MR-pathologic comparisons of wallerian degeneration in spinal cord injury. AJNR Am J Neuroradiol 1995; 16: 125-33.
Bovolenta P, Wandosell F, Nieto-Sampedro M. Neurite outgrowth inhibitors associated with glial cells and glial cell lines. Neuroreport 1993; 5: 345-8.
Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 2002; 416: 636-40.
Bruce JH, Norenberg MD, Kraydieh S, Puckett W, Marcillo A, Dietrich D. Schwannosis: role of gliosis and proteoglycan in human spinal cord injury. J Neurotrauma 2000; 17: 781-8.
Bruck W. The role of macrophages in Wallerian degeneration. Brain Pathol 1997; 7: 741-52.
Bunge RP, Puckett WR, Hiester ED. Observations on the pathology of several types of human spinal cord injury, with emphasis on the astrocyte response to penetrating injuries. Adv Neurol 1997; 72: 305-15.
Buss A, Schwab ME. Sequential loss of myelin proteins during Wallerian degeneration in the rat spinal cord. Glia 2003; 42: 424-32.
Coleman M, Perry V. Axon pathology in neurological disease: a neglected therapeutic target. Trends Neurosci 2002; 25: 532-7.
Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Beattie MS. Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med 1997; 3: 73-6.
Davies SJ, Fitch MT, Memberg SP, Hall AK, Raisman G, Silver J. Regeneration of adult axons in white matter tracts of the central nervous system. Nature 1997; 390: 680-3.
Davies SJ, Goucher DR, Doller C, Silver J. Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J Neurosci 1999; 19: 5810-22.
Fawcett JW, Asher RA. The glial scar and central nervous system repair. Brain Res Bull 1999; 49: 377-91.
Fernaud-Espinosa I, Nieto-Sampedro M, Bovolenta P. Differential activation of microglia and astrocytes in aniso- and isomorphic gliotic tissue. Glia 1993; 8: 277-91.
Fitch MT, Silver J. Activated macrophages and the blood-brain barrier: inflammation after CNS injury leads to increases in putative inhibitory molecules. Exp Neurol 1997; 148: 587-603.
Franson P, Ronnevi LO. Myelin breakdown and elimination in the posterior funiculus of the adult cat after dorsal rhizotomy: a light and electron microscopic qualitative and quantitative study. J Comp Neurol 1984; 223: 138-51.
George R, Griffin JW. The proximo-distal spread of axonal degeneration in the dorsal columns of the rat. J Neurocytol 1994; 23: 657-67.
Giulian D, Li J, Li X, George J, Rutecki PA. The impact of microglia-derived cytokines upon gliosis in the CNS. Dev Neurosci 1994; 16: 128-36.
Hatten ME, Liem RK, Shelanski ML, Mason CA. Astroglia in CNS injury. Glia 1991; 4: 233-43.
Jones LL, Tuszynski MH. Spinal cord injury elicits expression of keratan sulfate proteoglycans by macrophages, reactive microglia, and oligodendrocyte progenitors. J Neurosci 2002; 22: 4611-24.
Jones LL, Yamaguchi Y, Stallcup WB, Tuszynski MH. NG2 is a major chondroitin sulfate proteoglycan produced after spinal cord injury and is expressed by macrophages and oligodendrocyte progenitors. J Neurosci 2002; 22: 2792-803.
Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996; 19: 312-8.
Levenson D, Rosenbluth J. Electrophysiologic changes accompanying Wallerian degeneration in frog sciatic nerve. Brain Res 1990; 523: 230-6.
Li Y, Field PM, Raisman G. Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 1997; 277: 2000-2.
Liu BP, Fournier A, GrandPre T, Strittmatter SM. Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 2002; 297: 1190-3.
Liu Y, Kim D, Himes BT, Chow SY, Schallert T, Murray M, et al. Transplants of fibroblasts genetically modified to express BDNF promote regeneration of adult rat rubrospinal axons and recovery of forelimb function. J Neurosci 1999; 19: 4370-87.
Lubinska L. Early course of Wallerian degeneration in myelinated fibres of the rat phrenic nerve. Brain Res 1977; 130: 47-63.
Mansour H, Asher R, Dahl D, Labkovsky B, Perides G, Bignami A. Permissive and non-permissive reactive astrocytes: immunofluorescence study with antibodies to the glial hyaluronate-binding protein. J Neurosci Res 1990; 25: 300-11.
Miklossy J, Van der Loos H. The long-distance effects of brain lesions: visualization of myelinated pathways in the human brain using polarizing and fluorescence microscopy. J Neuropathol Exp Neurolol 1991; 50: 1-15.
Miledi R, Slater CR. On the degeneration of rat neuromuscular junctions after nerve section. J Physiol 1970; 207: 507-28.
Moon LD, Asher RA, Rhodes KE, Fawcett JW. Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat Neurosci 2001; 4: 465-6.
Morgenstern DA, Asher RA, Fawcett JW. Chondroitin sulphate proteoglycans in the CNS injury response. Prog Brain Res 2002; 137: 313-32.
Norenberg MD. Reactive astrocytosis. In: Aschner M, Kimelberg HK, editors. The role of glia in neurotoxicity. Boca Raton (FL): CRC Press; 1996. p. 93-107.
Puckett WR, Hiester ED, Norenberg MD, Marcillo AE, Bunge RP. The astroglial response to Wallerian degeneration after spinal cord injury in humans. Exp Neurol 1997; 148: 424-32.
Ramon-Cueto A, Cordero MI, Santos-Benito FF, Avila J. Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron 2000; 25: 425-35.
Reier PJ, Stensaas LJ, Guth L. The astrocytic scar as an impediment to regeneration in the central nervous system. In: Kao CC, Bunge RP, Reier PJ, editors. Spinal cord reconstruction. New York (NY): Raven Press; 1983. p. 162-95.
Ridet JL, Malhotra SK, Privat A, Gage FH. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 1997; 20: 570-7.
Schafer M, Fruttiger M, Montag D, Schachner M, Martini R. Disruption of the gene for the myelin-associated glycoprotein improves axonal regrowth along myelin in C57BL/Wlds mice. Neuron 1996; 16: 1107-13.
Schmitt AB, Brook GA, Buss A, Nacimiento W, Noth J, Kreutzberg GW. Dynamics of microglial activation in the spinal cord after cerebral infarction are revealed by expression of MHC class II antigen. Neuropathol Appl Neurobiol 1998; 24: 167-76.
Schmitt AB, Buss A, Breuer S, Brook GA, Pech K, Martin D, et al. Major histocompatibility complex class II expression by activated microglia caudal to lesions of descending tracts in the human spinal cord is not associated with a T cell response. Acta Neuropathol (Berl) 2000; 100: 528-36.
Schwab ME, Bartholdi D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev 1996; 76: 319-70.
Shuman SL, Bresnahan JC, Beattie MS. Apoptosis of microglia and oligodendrocytes after spinal cord contusion in rats. J Neurosci Res 1997; 50: 798-808.
Simonen M, Pedersen V, Weinmann O, Schnell L, Buss A, Ledermann B, et al. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron 2003; 38: 201-11.
Stichel CC, Hermanns S, Luhmann HJ, Lausberg F, Niermann H, D'Urso D, et al. Inhibition of collagen IV deposition promotes regeneration of injured CNS axons. Eur J Neurosci 1999; 11: 632-46.
Tuszynski MH, Grill R, Jones LL, Brant A, Blesch A, Low K, et al. NT-3 gene delivery elicits growth of chronically injured corticospinal axons and modestly improves functional deficits after chronic scar resection. Exp Neurol 2003; 181: 47-56.
Waller A. Experiments on the section of glossopharyngeal and hypoglossal nerves of the frog and observations of the alternatives produced thereby in the structure of their primitive fibres. Phil Trans R Soc Lond 1850; 140: 423.
Wang KC, Koprivica V, Kim JA, Sivasankaran R, Guo Y, Neve RL, et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 2002; 417: 941-4.