Conversion of Aβ43 to Aβ40 by the Successive Action of Angiotensin-Converting Enzyme 2 and Angiotensin-Converting Enzyme

The longer and neurotoxic species of amyloid-beta protein (A beta), A beta 42 and A beta 43, contribute to A beta 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 A beta, A beta 40, inhibits amyloid deposition and may have neuroprotective effects. We have reported that angiotensin-converting enzyme (ACE) converts A beta 42 to A beta 40 and that A beta 43 is the earliest-depositing A beta species in the amyloid precursor protein transgenic mouse brain. Here we found that A beta 43 can be converted to A beta 42 and to A beta 40 in mouse brain lysate. We further identified the brain A beta 43-to-A beta 42-converting enzyme as ACE2. The purified human ACE2 converted A beta 43 to A beta 42, and this activity was inhibited by a specific ACE2 inhibitor, DX600. Notably, the combination of ACE2 and ACE could convert A beta 43 to A beta 40. Our results indicate that the longer, neurotoxic forms of A beta can be converted to the shorter, less toxic or neuroprotective forms of A beta 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. (C) 2014 Wiley Periodicals, Inc.