PROTEOLYTIC DEGRADATION OF ALZHEIMERS-DISEASE AMYLOID BETA-PEPTIDE BYA METALLOPROTEINASE FROM MICROGLIA CELLS

The cerebral deposition of amyloid beta-peptide (A beta) is a histopat hological characteristic of Alzheimer's disease, Because an impaired c learance of A beta might be involved in the disease, we investigated t he proteolytic degradation of synthetic A beta (40-residue peptide) in cultures of glial cells and characterized a protease involved. Wherea s rat astrocytes had a very low degradation capacity, cultivated rat m icroglia cells cleaved A beta. Microglia activity was considerably enh anced by stimulation with lipopolysaccharide and to a lesser extent by phorbol esters, Most of the A beta-degrading activity was released in to the medium. By use of selective inhibitors the protease was charact erized as a metalloprotease of similar to 200 kDa that was different f rom neutral endopeptidase (a neuropeptide-degrading enzyme), matrix me talloproteases, or macrophage elastase, Its activity was efficiently r educed by four hydroxamic acid-based zinc-metalloprotease inhibitors t hat have been shown to inhibit membrane protein secretases (disintegri ns). We conclude that activated microglia cells might impair amyloid p laque formation by release of a metalloprotease that degrades soluble A beta before polymerization.