The cerebral deposition of amyloid beta-peptide (A beta) is a histopathological characteristic of Alzheimer's disease. Because an impaired clearance of A beta might be involved in the disease, we investigated the proteolytic degradation of synthetic A beta (40-residue peptide) in cultures of glial cells and characterized a protease involved. Whereas rat astrocytes had a very low degradation capacity, cultivated rat microglia cells cleaved A beta. Microglia activity was considerably enhanced by stimulation with lipopolysaccharide and to a lesser extent by phorbol esters. Most of the A beta-degrading activity was released into the medium. By use of selective inhibitors the protease was characterized as a metalloprotease of approximately 200 kDa that was different from neutral endopeptidase (a neuropeptide-degrading enzyme), matrix metalloproteases, or macrophage elastase. Its activity was efficiently reduced by four hydroxamic acid-based zinc-metalloprotease inhibitors that have been shown to inhibit membrane protein secretases (disintegrins). We conclude that activated microglia cells might impair amyloid plaque formation by release of a metalloprotease that degrades soluble A beta, before polymerization.