Inhibition of Amyloid β-Protein Production in Neural Cells by the Serine Protease Inhibitor AEBSF

Abstract

Cerebral deposition of amyloid β protein (Aβ) is an early and critical feature of Alzheimer's disease. Aβ production requires the proteolytic release of Aβ from the β-amyloid precursor protein (βAPP). Thus, inhibition of Aβ release is a prime therapeutic goal. Here, we show that the broad spectrum, irreversible serine protease inhibitor, AEBSF, inhibits the constitutive production of Aβ in five different human cell lines, both neural and nonneural. AEBSF also stabilizes full-length βAPP and enhances α-secretion, as shown by an increase in the proteolytic derivative, α-APPs. Further, we demonstrate that the inhibitory effect of AEBSF is specific for Aβ proteins starting at Aspartate 1, suggesting that AEBSF directly inhibits β-secretase, the Methionine–Aspartate (Met–Asp)-cleaving enzyme. These results indicate that specific inhibition of this Aβ-generating protease is possible in living human neural cells and provide information about the characteristics of this as yet unidentified enzyme.