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