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.