Microglial Proteases: Strategic Targets for Neuroprotective Agents

There is growing evidence that proteolytic systems of microglia are closely associated with both their protective and cytotoxic roles in the central nervous system (CNS). Cathepsin E and cathepsin S have been shown to play important roles in the major histocompatibility complex (MHC) class II-mediated antigen presentation of microglia. On the other hand, proteasome is required for MHC class-I-mediated antigen presentation of microglia during viral and bacterial infections in the CNS. Several recent studies have suggested an involvement of cathepsin D and insulin-degrading enzyme in the clearance of amyloid-β peptides by microglia. Furthermore, attention has been also paid to the deleterious effects of proteases secreted from microglia. Besides having roles in the endosomal / lysosomal system, cathepsin S and cathepsin B secreted from microglia are also found to be responsible for microglia-induced tissue damage and neuronal death. Tissue-type plasminogen activator secreted from microglia also participates in neuronal death, an enhancement of N-methyl-D-aspartate receptor-mediated synaptic transmission, and an activation of microglia. Calpain has been demonstrated to play a pivotal role in the pathogenesis of multiple sclerosis by degrading myelin proteins extracellulary. Furthermore, matrix metalloproteases secreted from microglia contribute to the cerebrovascular diseases by degrading components of the basal lamina around the cerebral blood vessels.In this review, I have focused on the proteolytic systems that are associated with the protective and cytotoxic roles of microglia in the CNS. The understanding of proteolytic events mediated by microglial proteases may also aid in the development of protease inhibitors as the novel neuroprotective agents.