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J. Biol. Chem., Vol. 280, Issue 45, 37644-37650, November 11, 2005

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

From the Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Human genetic data have associated angiotensin-converting enzyme (ACE) with Alzheimer disease (AD), and purified ACE has been reported to cleave synthetic amyloid -protein (A) in vitro. Whether deficiency in ACE activity, arising from genetic alteration or pharmacological inhibition, can decrease A degradation and allow A 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 A40 and A42, leading to significant clearance of both species. Using site-directed mutagenesis, we determined that both active sites within ACE contribute to A clearance, and an ACE construct bearing mutations in each catalytic domain had no effect on A levels. Pharmacological inhibition of ACE with a widely prescribed drug, captopril, promoted the accumulation of cell-derived A in the media of -amyloid precursor-protein expressing cells. Together, these results show that ACE can lower the levels of secreted A 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 A. 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 A levels in humans.

Received for publication, August 2, 2005 , and in revised form, September 8, 2005.

^* This work was supported by National Institutes of Health Grant AG12749 (to D. J. S.) and a predoctoral fellowship from the Harvard Center for Neurodegeneration and Repair (to M. L. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Harvard Institutes of Medicine 730, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-525-5200; Fax: 617-525-5252; E-mail: dselkoe{at}rics.bwh.harvard.edu.

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