Angiotensin-Converting Enzyme Converts Amyloid β-Protein 1–42 (Aβ_1–42) to Aβ_1–40, 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 Aβ 1–42 is a cause of neuronal damage leading to AD pathogenesis and that monomeric Aβ 1–40 has less neurotoxicity than Aβ 1–42 . We found that mouse and human brain homogenates exhibit an enzyme activity converting Aβ 1–42 to Aβ 1–40 and that the major part of this converting activity is mediated by the angiotensin-converting enzyme (ACE). Purified human ACE converts Aβ 1–42 to Aβ 1–40 as well as decreases Aβ 1–42 /Aβ 1–40 ratio and degrades Aβ 1–42 and Aβ 1–40 . Importantly, the treatment of Tg2576 mice with an ACE inhibitor, captopril, promotes predominant Aβ 1–42 deposition in the brain, suggesting that ACE regulates Aβ 1–42 /Aβ 1–40 ratio in vivo by converting secreted Aβ 1–42 to Aβ 1–40 and degrading Aβs. The upregulation of ACE activity can be a novel therapeutic strategy for AD.