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

Abstract

Amyloid ␤-protein 1-42 (A␤42) is believed to play a causative role in the development of Alzheimer disease (AD), although it is a minor part of A␤. In contrast, A␤40 is the predominant secreted form of A␤ and recent studies have suggested that A␤40 has neuroprotective effects and inhibits amyloid deposition. We have reported that angiotensin-converting enzyme (ACE) converts A␤42 to A␤40, and its inhibition enhances brain A␤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␤42 to A␤40. Interestingly, A␤42-to-A␤40-converting activity is solely found in the N-domain of ACE and the angiotensinconverting activity is found predominantly in the C-domain of ACE. We also found that the N-linked glycosylation is essential for both A␤42-to-A␤40-and angiotensin-converting activities and that unglycosylated ACE rapidly degraded. The domainspecific converting activity of ACE suggests that ACE inhibitors could be designed to specifically target the angiotensin-converting C-domain, without inhibiting the A␤42-to-A␤40-converting activity of ACE or increasing neurotoxic A␤42. Angiotensin-converting enzyme (ACE)4 plays a key role in the renin-angiotensin system (RAS), which is involved in the long-term regulation of blood pressure and blood volume in the human body. Recent genetic, pathologic, and biochemical studies have associated ACE with onset of Alzheimer disease (AD) (1, 2). The I allele of the ACE gene, which results in a reduced serum ACE level, has been demonstrated to be associated with AD (3-5). Hypertension is a risk factor for AD and ACE inhibitors for treatment of hypertension were shown to be the only drug class among the antihypertensives to potentially be associated with a slight increased incidence of AD (adjusted hazard ratio 1.13) (6, 7). A mechanistic link between ACE and AD was suggested when ACE was shown to degrade A␤40 and A␤42 (8, 9). Overexpression of A␤40 in transgenic mice does not cause brain amyloid deposition, the major pathological hallmark of AD, whereas expression of A␤42 is shown to be essential for amyloid deposition (10, 11). In addition, A␤40 has an inhibitory effect on amyloid deposition in vitro and in vivo and has neuroprotective effects (12)(13)(14). These lines of evidence suggest that converting A␤42 to A␤40 may be a potential strategy for development of an AD therapy. In our previous study, we identified ACE as an A␤42-to-A␤40-converting (A␤-converting) enzyme and showed that ACE inhibitor enhances brain A␤42 deposition in transgenic mice (15). Clarifying the molecular base of ACE domain-specific enzymatic activity on A␤42 to A␤40 conversion, A␤ degradation, and angiotensin conversion emerges to be important for development of a strategy for hypertension and AD treatment.AC...

Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline

“…Several studies have identified ACE as being capable of cleaving a variety of amyloid peptides, including Aβ 1-42 and Aβ , into smaller fragments; at least in vitro, ACE can have both carboxypeptidic and endopeptidic activity against these larger amyloidogenic peptides (20)(21)(22)63). In ACE 10/10 mice, the serum levels of ACE are no different from WT mice.…”

“…Studies have suggested that ACE not only converts Aβ 1-42 to Aβ 1-40 but can also cleave Aβ 1-40 into smaller fragments (20)(21)(22). Cerebral levels of Aβ were measured by ELISA in 7-month-old…”

“…However, ACE is a fairly nonspecific peptidase that has been shown to hydrolyze peptides as small as three amino acids and as large as Aβ (20)(21)(22). While large amounts of ACE are made by vascular endothelium, virtually every tissue makes some ACE (23).…”

Angiotensin converting enzyme and Alzheimer’s disease

“…2) [81]. In vitro experi ments also demonstrated that only the N domain of ACE contributes to conversion of Aβ to Aβ and the ACEI enalapril was the most potent inhibitor of this process (compared with captopril, perindopril, and lisinopril) [82].…”

Angiotensin converting enzyme and Alzheimer's disease

“…Эксперименты, проведенные in vitro показали, что отщепление двух последних а.о. от Аb осуществляется N-доменом АПФ, а так же то, что самым сильным тормозящим действием на этот процесс обладает иАПФ эналаприл (по сравнению с каптоприлом, периндоприлом и лизиноприлом) [82].…”