Amyloid β-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor

Abstract

Human genetic data have associated angiotensin-converting enzyme (ACE) with Alzheimer disease (AD), and purified ACE has been reported to cleave synthetic amyloid β-protein (Aβ) in vitro. Whether deficiency in ACE activity, arising from genetic alteration or pharmacological inhibition, can decrease Aβ degradation and allow Aβ accumulation in intact cells is unknown. We cloned ACE from human neuroblastoma cells and showed that it had posttranslational processing and enzymatic activity typical of the endogenous protease. Cellular expression of ACE promoted degradation of naturally secreted Aβ40 and Aβ42, leading to significant clearance of both species. Using site-directed mutagenesis, we determined that both active sites within ACE contribute to Aβ clearance, and an ACE construct bearing mutations in each catalytic domain had no effect on Aβ levels. Pharmacological inhibition of ACE with a widely prescribed drug, captopril, promoted the accumulation of cell-derived Aβ in the media of β-amyloid precursor-protein expressing cells. Together, these results show that ACE can lower the levels of secreted Aβ in living cells and that this effect is blocked by inhibiting the protease's activity with an ACE inhibitor. This work, combined with the genetic studies, supports the hypothesis that ACE may modulate the susceptibility to and progression of AD via degradation of Aβ. Our data encourage further analyses of the ACE gene for disease association and raise the question of whether currently prescribed ACE inhibitors could elevate cerebral Aβ levels in humans. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.