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J. Biol. Chem., Vol. 281, Issue 41, 30471-30478, October 13, 2006

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Regulation of Steady-state -Amyloid Levels in the Brain by Neprilysin and Endothelin-converting Enzyme but Not Angiotensin-converting Enzyme^*

Elizabeth A. Eckman, Stephanie K. Adams, Frederick J. Troendle, Becky A. Stodola, Murad A. Kahn, Abdul H. Fauq, Hong D. Xiao, Kenneth E. Bernstein, and Christopher B. Eckman¹

From the Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224 and the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322

The deposition of -amyloid in the brain is a pathological hallmark of Alzheimer disease (AD). Normally, the accumulation of -amyloid is prevented in part by the activities of several degradative enzymes, including the endothelin-converting enzymes, neprilysin, insulin-degrading enzyme, and plasmin. Recent reports indicate that another metalloprotease, angiotensin-converting enzyme (ACE), can degrade -amyloid in vitro and in cellular overexpression experiments. In addition, ACE gene variants are linked to AD risk in several populations. Angiotensin-converting enzyme, neprilysin and endothelin-converting enzyme function as vasopeptidases and are the targets of drugs designed to treat cardiovascular disorders, and ACE inhibitors are commonly prescribed. We investigated the potential physiological role of ACE in regulating endogenous brain -amyloid levels for two reasons: first, to determine whether -amyloid degradation might be the mechanism by which ACE is associated with AD, and second, to determine whether ACE inhibitor drugs might block -amyloid degradation in the brain and potentially increase the risk for AD. We analyzed -amyloid accumulation in brains from ACE-deficient mice and in mice treated with ACE inhibitors and found that ACE deficiency did not alter steady-state -amyloid concentration. In contrast, -amyloid levels are significantly elevated in endothelin-converting enzyme and neprilysin knock-out mice, and inhibitors of these enzymes cause a rapid increase in -amyloid concentration in the brain. The results of these studies do not support a physiological role for ACE in the degradation of -amyloid in the brain but confirm roles for endothelin-converting enzyme and neprilysin and indicate that reductions in these enzymes result in additive increases in brain amyloid -peptide levels.

Received for publication, June 19, 2006 , and in revised form, August 9, 2006.

^* This work was supported by NINDS, National Institutes of Health Grants R01NS042192 and R01NS048554 and by the Mayo Foundation for Medical Education and Research. 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: Dept. of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Rd., Jacksonville, FL 32224. Tel.: 904-953-2979; Fax: 904-953-7370; E-mail: eckman{at}mayo.edu.

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