beta-Amyloid peptide produced in vitro is degraded by proteinases released by cultured cells.

The primary histopathological feature of Alzheimer's disease is the accumulation of beta-amyloid in the brains of afflicted individuals. This peptide has been shown to be produced and liberated both in vitro and in vivo by normal physiological processes. The mechanism by which beta-amyloid is formed, as well as that by which it may be cleared, are events likely to impact on the development and progression of this disease. Thus, the fate of beta-amyloid peptides secreted by cultured mammalian cells was investigated. It was found that levels of the soluble peptide are reduced over time due to the activity of multiple types of proteinases including those from the metallo, aspartyl, and thiol classes. Inhibitors to each class of proteinase can only partially block beta-amyloid degradation, but, if used in combination, they can fully prevent its catabolism. The Kunitz serine proteinase inhibitor domain, present on two beta-amyloid precursor protein isoforms, was found to be an effective inhibitor of beta-amyloid peptide degradation. These data indicate that modulations in expression of secreted proteinases and/or beta-amyloid precursor isoforms may influence levels of beta-amyloid.