Amyloid ␤-protein (A␤) is the major component of neuritic (amyloid) plaques in Alzheimer's disease, and its deposition is an early and constant event in the complex pathogenetic cascade of the disease. Although many studies have focused on the biosynthetic processing of the ␤-amyloid precursor protein and on the production and polymerization of A␤, understanding the degradation and clearance of A␤ has received very little attention. By incubating the conditioned medium of metabolically labeled

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... ␤-secreting cells with media of various cultured cell lines, we observed a time-dependent decrease in the amount of A␤ in the mixed media. The factor principally responsible for this decrease was a secreted metalloprotease released by both neural and non-neural cells. Among the cells examined, the microglial cell line, BV-2, produced the most A␤-degrading activity. The protease was completely blocked by the metalloprotease inhibitor, 1,10-phenanthroline, and partially inhibited by EDTA, whereas inhibitors of other protease classes produced little or no inhibition. Substrate analysis suggests that the enzyme was a non-matrix metalloprotease. The protease cleaved both A␤ 1-40 and A␤ 1-42 peptides secreted by ␤-amyloid precursor protein-transfected cells but failed to degrade low molecular weight oligomers of A␤ that form in the culture medium. Lipopolysaccharide, a stimulator of macrophages/microglia, activated BV-2 cells to increase their A␤-degrading metalloprotease activity. We conclude that secreted A␤ 1-40 and A␤ 1-42 peptides are constitutively degraded by a metalloprotease released by microglia and other neural cells, providing a potential mechanism for the clearance of A␤ in brain tissue.