Aβ42-to-Aβ40-and Angiotensin-converting Activities in Different Domains of Angiotensin-converting Enzyme

Amyloid beta-protein 1-42 (A beta 42) is believed to play a causative role in the development of Alzheimer disease (AD), although it is a minor part of A beta. In contrast, A beta 40 is the predominant secreted form of A beta and recent studies have suggested that A beta 40 has neuroprotective effects and inhibits amyloid deposition. We have reported that angiotensin-converting enzyme (ACE) converts A beta 42 to A beta 40, and its inhibition enhances brain A beta 42 deposition (Zou, K., Yamaguchi, H., Akatsu, H., Sakamoto, T., Ko, M., Mizoguchi, K., Gong, J. S., Yu, W., Yamamoto, T., Kosaka, K., Yanagisawa, K., and Michikawa, M. (2007) J. Neurosci. 27, 8628-8635). ACE has two homologous domains, each having a functional active site. In the present study, we identified the domain of ACE, which is responsible for converting A beta 42 to A beta 40. Interestingly, A beta 42-to-A beta 40-converting activity is solely found in the N-domain of ACE and the angiotensin-converting activity is found predominantly in the C-domain of ACE. We also found that the N-linked glycosylation is essential for both A beta 42-to-A beta 40- and angiotensin-converting activities and that unglycosylated ACE rapidly degraded. The domain-specific converting activity of ACE suggests that ACE inhibitors could be designed to specifically target the angiotensin-converting C-domain, without inhibiting the A beta 42-to-A beta 40-converting activity of ACE or increasing neurotoxic A beta 42.