Conversion of Aß43 to Aß40 by the successive action of angiotensin-converting enzyme 2 and angiotensin-converting enzyme.

ABSTRACT

The longer and neurotoxic species of amyloid-ß protein (Aß), Aß42 and Aß43, contribute to Aß 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 Aß, Aß40, inhibits amyloid deposition and may have neuroprotective effects. We have reported that angiotensin-converting enzyme (ACE) converts Aß42 to Aß40 and that Aß43 is the earliest-depositing Aß species in the amyloid precursor protein transgenic mouse brain. Here we found that Aß43 can be converted to Aß42 and to Aß40 in mouse brain lysate. We further identified the brain Aß43-to-Aß42-converting enzyme as ACE2. The purified human ACE2 converted Aß43 to Aß42, and this activity was inhibited by a specific ACE2 inhibitor, DX600. Notably, the combination of ACE2 and ACE could convert Aß43 to Aß40. Our results indicate that the longer, neurotoxic forms of Aß can be converted to the shorter, less toxic or neuroprotective forms of Aß 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.