Myelin Loss Does Not Lead to Axonal Degeneration in a Long-Lived Model of Chronic Demyelination

Abstract

Current dogma suggests that chronically demyelinated axons are at risk for degeneration, with axonal loss resulting in permanent disability in myelin disease. However, the trophic role of the myelin sheath in long-term axonal survival is incompletely understood. Previous observations of the effect of dysmyelination or demyelination on axonal survival in the myelin mutants has been limited because of their short life span. In this study, we used the Long-Evans shaker (les) rat, which can live up to 9 months, to study axonal health and survival after chronic demyelination. At 2 weeks, ∼29% of medium and ∼47% of large fiber axons are myelinated in les spinal cord. However, by 3 months, no medium and ∼<1% of large-diameter axons retain myelin. After demyelination, axons have a reduced-caliber, abnormal neurofilament distribution and an increase in mitochondrial number. However, there are no signs of axonal degeneration in les rats up to 9 months. Instead, there is a profound increase in oligodendrocytes, which were found to express BDNF, NT-3, and IGF-1. Importantly, this study provides in vivo evidence that mature glial cells produce various neurotrophic factors that may aid in the survival of axons after chronic demyelination.