Angiotensin-converting enzyme converts amyloid β-protein 1-42 (Aβ1-42) to Aβ1-40, and its inhibition enhances brain Aβ deposition

Abstract

The abnormal deposition of the amyloid β-protein (Aβ) in the brain appears crucial to the pathogenesis of Alzheimer's disease (AD). Recent studies have suggested that highly amyloidogenic Aβ1-42 is a cause of neuronal damage leading to AD pathogenesis and that monomeric Aβ1-40 has less neurotoxicity than Aβ1-42. We found that mouse and human brain homogenates exhibit an enzyme activity converting Aβ1-42 to Aβ1-40 and that the major part of this converting activity is mediated by the angiotensin-converting enzyme (ACE). Purified human ACE converts Aβ1-42 to Aβ1-40 as well as decreases Aβ1-42/ Aβ1-40 ratio and degrades Aβ1-42 and Aβ1-40. Importantly, the treatment of Tg2576 mice with an ACE inhibitor, captopril, promotes predominant Aβ1-42 deposition in the brain, suggesting that ACE regulates Aβ1-42/Aβ 1-40 ratio in vivo by converting secreted Aβ1-42 to Aβ1-40 and degrading Aβs. The upregulation of ACE activity can be a novel therapeutic strategy for AD. Copyright © 2007 Society for Neuroscience.