We have demonstrated that the angiotensin-converting enzyme (ACE) genotype is associated with Alzheimer's disease (AD) in the Japanese population (). To determine why ACE affects susceptibility to AD, we examined the effect of purified ACE on aggregation of the amyloid beta-peptide (A beta) in vitro. Surprisingly, ACE was found to significantly inhibit A beta aggregation in a dose response manner. The inhibition of aggregation was specifically blocked by preincubation of ACE with an ACE inhibitor, lisinopril. ACE was confirmed to retard A beta fibril formation with electron microscopy. ACE inhibited A beta deposits on a synthaloid plate, which was used to monitor A beta deposition on autopsied brain tissue. ACE also significantly inhibited A beta cytotoxicity on PC12 h. The most striking fact was that ACE degraded A beta by cleaving A beta-(1-40) at the site Asp(7)-Ser(8). This was proven with reverse-phase HPLC, amino acid sequence analysis, and MALDI-TOF/MS. Compared with A beta-(1-40), aggregation and cytotoxic effects of the degradation products A beta-(1-7) and A beta-(8-40) peptides were reduced or virtually absent. These findings led to the hypothesis that ACE may affect susceptibility to AD by degrading A beta and preventing the accumulation of amyloid plaques in vivo.