Slowly progressive axonal degeneration in a rat model of chronic, nonimmune-mediated demyelination

Axonal degeneration in the central nervous system (CNS) is associated with neurologic disability. In some diseases, it has been postulated that axonal degeneration may be caused by loss of trophic support normally provided by oligodendrocytes and myelin. To investigate this phenomenon, we studied axonal pathology in the taiep mutant rat, which develops nonimmune oligodendrocyte dysfunction and myelin loss. Using immunohistochemical analysis of several CNS regions, we show that accumulation of dephosphorylated neurofilaments occurs in taiep axons. These changes become more pronounced as myelin loss increases and characteristic spheroids, representing transected axons, become abundant. Amyloid precursor protein staining is increased in taiep white matter tracts, indicating abnormalities of axonal transport. These changes do not occur in wild type controls. Optic nerve counts demonstrate progressive axonal loss throughout the life of the rat; early axonal loss occurs in the context of dysmyelination; later axonal loss is likely to be related to chronic demyelination. The axonal pathology in the taiep rat provides evidence that CNS axonopathy may, in certain situations, be related to a loss of trophic support normally provided by cells of the oligodendrocyte lineage and/or myelin; this may occur in the absence of significant inflammation.