Conversion of Aβ43 to Aβ40 by the successive action of angiotensin‐converting enzyme 2 and angiotensin‐converting enzyme

Abstract

The longer and neurotoxic species of amyloid‐β protein (Aβ), Aβ42 and Aβ43, contribute to Aβ accumulation in Alzheimer's disease (AD) pathogenesis and are considered to be the primary cause of the disease. In contrast, the predominant secreted form of Aβ, Aβ40, inhibits amyloid deposition and may have neuroprotective effects. We have reported that angiotensin‐converting enzyme (ACE) converts Aβ42 to Aβ40 and that Aβ43 is the earliest‐depositing Aβ species in the amyloid precursor protein transgenic mouse brain. Here we found that Aβ43 can be converted to Aβ42 and to Aβ40 in mouse brain lysate. We further identified the brain Aβ43‐to‐Aβ42‐converting enzyme as ACE2. The purified human ACE2 converted Aβ43 to Aβ42, and this activity was inhibited by a specific ACE2 inhibitor, DX600. Notably, the combination of ACE2 and ACE could convert Aβ43 to Aβ40. Our results indicate that the longer, neurotoxic forms of Aβ can be converted to the shorter, less toxic or neuroprotective forms of Aβ by ACE2 and ACE. Moreover, we found that ACE2 activity showed a tendency to decrease in the serum of AD patients compared with normal controls, suggesting an association between lower ACE2 activity and AD. Thus, maintaining brain ACE2 and ACE activities may be important for preventing brain amyloid neurotoxicity and deposition in Alzheimer's disease. © 2014 Wiley Periodicals, Inc.

Deficiency of angiotensin-converting enzyme 2 causes deterioration of cognitive function

“…Ang-(1–7) has also been reported to exert a protective role against blood–brain barrier damage through the balance of tissue inhibitor of metalloproteinase 1 and matrix metalloproteinase-9 hemopexin domain. 36 Moreover, Liu et al 37 found that Aβ43 was able to be converted into Aβ42 and Aβ40 in mouse brain lysates, and identified the brain Aβ43-to-Aβ42-converting enzyme to be ACE2. They also reported that ACE2 tended to decrease in the serum of Alzheimer's disease patients compared with normal controls.…”

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

“…However, ACE2 displays a different specificity from ACE acting as a monocarboxypeptidase (Turner, Tipnis, Guy, Rice, & Hooper, ), but it does have activity on some amyloid peptides but not Aβ40 or Aβ42. In particular, it can convert Aβ43 to Aβ42, which can then be further metabolized by ACE to the less amyloidogenic Aβ40 (Liu et al, ). More recently, the ACE2 activator diminazene was shown to induce stimulation of the ACE2/angiotensin(1‐7)/mas axis reducing cognitive deficits in AD, most probably through activation of the PI3K/Akt pathway (Kamel et al, ).…”

Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology

“…Previous studies have suggested a link between reduced activity of the ACE-2/Ang (1-7)/Mas axis and neurodegenerative conditions, including multiple sclerosis [36]. A recent study provided the first clues of an association with AD and reported reduced serum ACE-2 activity in patients with AD compared with control subjects [37]. Notably, this study also identified that ACE-2 converts Aβ 43 (an early deposited and highly amyloidogenic form of Aβ that seeds plaque formation [38]) to Aβ 42 , which in turn is cleaved by ACE-1 to less toxic Aβ 40 and Aβ 41 species [37].…”