Abstract
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder. Amyloid-β (Aβ) aggregation is likely to be the major cause of AD. In contrast to humans and other mammals, that share the same Aβ sequence, rats and mice are invulnerable to AD-like neurodegenerative pathologies, and Aβ of these rodents (ratAβ) has three amino acid substitutions in the metal-binding domain 1-16 (MBD). Angiotensin-converting enzyme (ACE) cleaves Aβ-derived peptide substrates, however, there are contradictions concerning the localization of the cleavage sites within Aβ and the roles of each of the two ACE catalytically active domains in the hydrolysis. In the current study by using mass spectrometry and molecular modelling we have tested a set of peptides corresponding to MBDs of Aβ and ratAβ to get insights on the interactions between ACE and these Aβ species. It has been shown that the N-domain of ACE (N-ACE) acts as an arginine specific endopeptidase on the Aβ and ratAβ MBDs with C-amidated termini, thus assuming that full-length Aβ and ratAβ can be hydrolyzed by N-ACE in the same endopeptidase mode. Taken together with the recent data on the molecular mechanism of zinc-dependent oligomerization of Aβ, our results suggest a modulating role of N-ACE in AD pathogenesis.
Highlights
Amyloid-β (Aβ) is a 39–43 amino acid long peptide heterogenic at the C-terminus (Aβ(1–39 ... 43)) and a normal component of biological fluids of humans and other mammals at picomolar concentration levels1
Since the majority of the reported angiotensin converting enzyme (ACE) cleavage sites27–32 are located in the Aβ N-terminal metal-binding domain 1DAEFRHDSGYEVHHQK16 (MBD)44–48, the synthetic MBD analogs with intact or modified N- and C-terimini would serve as adequate experimental ACE substrates
Products observed hydrolyzed only by the N-domain of ACE, which cleaves the Arg5-His6 bond, while the C-domain does not affect any of the bonds in this peptide32
Summary
Current data provides conflicting information on whether the active site of the N- or the C-domain participates in Aβ proteolysis, and whether ACE acts as an endopeptidase or a carboxypeptidase. All these uncertainties probably come from non-optimal peptide substrates used in the studies. In the current work using mass-spectrometry and molecular modelling we have tested a set of synthetic peptides (with free, as well as partially or fully protected termini) corresponding to Aβ MBD and ratAβ MBD (Table 1, Supplementary Fig. S1) as substrates for N- and C- domains of ACE to get more insights into the role of the interactions between ACE and Aβ in AD pathogenesis
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