Angiotensin-converting Enzyme Degrades Alzheimer Amyloid β-Peptide (Aβ); Retards Aβ Aggregation, Deposition, Fibril Formation; and Inhibits Cytotoxicity

Abstract

We have demonstrated that the angiotensin-converting enzyme (ACE) genotype is associated with Alzheimer's disease (AD) in the Japanese population (1). To determine why ACE affects susceptibility to AD, we examined the effect of purified ACE on aggregation of the amyloid β-peptide (Aβ) in vitro. Surprisingly, ACE was found to significantly inhibit Aβ 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 Aβ fibril formation with electron microscopy. ACE inhibited Aβ deposits on a synthaloid plate, which was used to monitor Aβ deposition on autopsied brain tissue. ACE also significantly inhibited Aβ cytotoxicity on PC12 h. The most striking fact was that ACE degraded Aβ by cleaving Aβ-(1-40) at the site Asp7-Ser8. This was proven with reverse-phase HPLC, amino acid sequence analysis, and MALDI-TOF/MS. Compared with Aβ-(1-40), aggregation and cytotoxic effects of the degradation products Aβ-(1-7) and Aβ-(8-40) peptides were reduced or virtually absent. These findings led to the hypothesis that ACE may affect susceptibility to AD by degrading Aβ and preventing the accumulation of amyloid plaques in vivo.