Activated microglia release -galactosidase that promotes inflammatory neurodegeneration

Beta (beta)-galactosidase is a lysosomal enzyme that removes terminal galactose residues from glycolipids and glycoproteins. It is upregulated in, and used as a marker for, senescent cells. Microglia are brain macrophages implicated in neurodegeneration, and can upregulate beta-galactosidase when senescent. We find that inflammatory activation of microglia induced by lipopolysaccharide results in translocation of beta-galactosidase to the cell surface and release into the medium. Similarly, microglia in aged mouse brains appear to have more beta-galactosidase on their surface. Addition of beta-galactosidase to neuronal-glial cultures causes microglial activation and neuronal loss mediated by microglia. Inhibition of beta-galactosidase in neuronal-glial cultures reduces inflammation and neuronal loss induced by lipopolysaccharide. Thus, activated microglia release beta-galactosidase that promotes microglial-mediated neurodegeneration which is prevented by inhibition of beta-galactosidase.