Amyloid β-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor

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 Aβ in the of that ACE can the of secreted Aβ in cells and that effect is the activity with an ACE with the genetic the that ACE the to and of degradation of data of the ACE disease and the of prescribed ACE Aβ in 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 Aβ in the of that ACE can the of secreted Aβ in cells and that effect is the activity with an ACE with the genetic the that ACE the to and of degradation of data of the ACE disease and the of prescribed ACE Aβ in and of Alzheimer disease is the accumulation and of the amyloid β-protein (Aβ) in and and data that Aβ is an of the disease and associated no to have on both the of Aβ and clearance from the to Aβ clearance is the degradation of the in the the enzyme and the and have each been in the has been in Aβ degradation in genetic deficiency accumulation of Aβ in a of the of or in a of Aβ and significant of angiotensin-converting enzyme (ACE) is a the and each of is active ACE has a domain and is from the a in the of the of cells and ACE has been in the of to and of ACE is ACE to the active to prescribed of is the of and to ACE a and it is to both and the and to and can ACE ACE to in the of ACE and human genetic reported that an within of the ACE with the associated with an the associated with of the has been associated with ACE disease the has been to with with or has been to of the and the of determined that with the had a with the in the ACE have been to with and is a decrease in the of the with with a of of with have of ACE in the and within ACE activity in the and ACE and ACE to synthetic the in a that and of the and is that ACE is in of the Aβ Aβ within the that ACE activity, genetic or pharmacological inhibition, of Aβ40 and the of contribute to in we cloned and human ACE and determined in the clearance of secreted that ACE the clearance of naturally Aβ40 and and to degradation of both Aβ species. site-directed in the of the we that both the and of ACE of Aβ degradation with we that of cells with a prescribed ACE Aβ clearance and in accumulation of the Aβ of ACE and of ACE of from the human neuroblastoma and to the and the ACE and and the ACE cloned the 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