P1‐160: Abeta42‐to‐abeta40‐ and angiotensin‐converting activities in different domains of angiotensin‐converting enzyme
Kun Zou, Tomoji Maeda, Ryutaro Oba, Makoto Michikawa, Hiroto Komano · Alzheimer s & Dementia · 2009
Amyloid β-protein 1-42 (Aβ42) is believed to play a causative role in the development of Alzheimer's disease (AD), although it is a minor part of Aβ. In contrast, Aβ40 is the predominant secreted form of Aβ and recent studies have suggested that Aβ40 has neuroprotective effects and inhibits amyloid deposition. We have reported that angiotensin-converting enzyme (ACE) converts Aβ42 to Aβ40 and its inhibition enhances brain Aβ42 deposition (Zou et al. J Neurosci, 2007). ACE is commonly targeted by ACE inhibitors for the treatment of hypertension in elderly populations and it has two homologous domains, each having a functional active site. We identified the domain of ACE which is responsible for converting Aβ42 to Aβ40 using N-domain, C-domain and both N- and C-domain recombinant proteins of ACE. Interestingly, we found that the Aβ42-to-Aβ40-converting and the angiotensin-converting activities are located in different domains of ACE. ACE domains select substrates and these results suggest that ACE inhibitors could be designed to specifically target the angiotensin-converting domain, without inhibiting the Aβ42-to-Aβ40-converting activity of ACE.