While proteolytic enzymes are involved in the pathogenesis of multiple sclerosis (MS), the involvement of cathepsins has not been characterized in detail. To better understand the role of cathepsins, cDNA microarray analysis was used to study the brains of proteolipid protein transgenic (plp ( tg ) /-) mice, an animal model that closely mimics the failure of remyelination in MS. Analysis revealed upregulated expression of cathepsins L, H and B and their inhibitor, cystatin C. By in situ hybridization, the induction of cathepsins was primarily limited to microglia/macrophages of the white matter, with continuous expression from 2 to 8 months of age. Elevated protein level of cathepsins was confirmed at 4 months of age. In contrast, elevated expression of cystatin C was found in astrocytes. The ratio of microglia/macrophages to astrocytes increased throughout the course of demyelination, suggesting that the ratio of secreted cathepsins to cystatin C increased during that period. We propose that in MS, remyelination may be impaired by increasing activity of cathepsins inadequately controlled by cystatin C.