INHIBITION OF AMYLOID BETA-PROTEIN PRODUCTION IN NEURAL CELLS BY THE SERINE-PROTEASE INHIBITOR AEBSF

Cerebral deposition of amyloid beta protein (A beta) is an early and c ritical feature of Alzheimer's disease. A beta production requires the proteolytic release of A beta from the beta-amyloid precursor protein (beta APP). Thus, inhibition of A beta release is a prime therapeutic goal. Here, we show that the broad spectrum, irreversible serine prot ease inhibitor, AEBSF, inhibits the constitutive production of A beta in five different human cell lines, both neural and nonneural. AEBSF a lso stabilizes full-length beta APP and enhances alpha-secretion, as s hown by an increase in the proteolytic derivative, alpha-APP(s). Furth er, we demonstrate that the inhibitory effect of AEBSF is specific for A beta proteins starting at Aspartate 1, suggesting that AEBSF direct ly inhibits beta-secretase, the Methionine-Aspartate (Met-Asp)-cleavin g enzyme. These results indicate that specific inhibition of this A be ta-generating protease is possible in living human neural cells and pr ovide information about the characteristics of this as yet unidentifie d enzyme.