Degradation of the Alzheimer's Amyloid β Peptide by Endothelin-converting Enzyme

Abstract

Deposition of ␤-amyloid (A␤) peptides in the brain is an early and invariant feature of all forms of Alzheimer's disease. As with any secreted protein, the extracellular concentration of A␤ is determined not only by its production but also by its catabolism. A major focus of Alzheimer's research has been the elucidation of the mechanisms responsible for the generation of A␤. Much less, however, is known about the mechanisms responsible for A␤ removal in the brain. In this report, we describe the identification of endothelin-converting enzyme-1 (ECE-1) as a novel A␤-degrading enzyme. We show that treatment of endogenous ECE-expressing cell lines with the metalloprotease inhibitor phosphoramidon causes a 2-3-fold elevation in extracellular A␤ concentration that appears to be due to inhibition of intracellular A␤ degradation. Furthermore, we show that overexpression of ECE-1 in Chinese hamster ovary cells, which lack endogenous ECE activity, reduces extracellular A␤ concentration by up to 90% and that this effect is completely reversed by treatment of the cells with phosphoramidon. Finally, we show that recombinant soluble ECE-1 is capable of hydrolyzing synthetic A␤40 and A␤42 in vitro at multiple sites.

Transthyretin binding to A‐Beta peptide – Impact on A‐Beta fibrillogenesis and toxicity

“…The total pool of A-Beta peptide depends not only of its production, by proteolytic processing of the precursor protein, but also of its removal. While there is some information elucidating the enzymes and pathways participating in peptide production, much less is known regarding A-Beta catabolism [30]. Our results have implicated TTR as an agent able to participate in the catabolism of the peptide, since it can interact with A-Beta contributing not only to maintenance of soluble A-Beta levels within normal range in the CSF but also to removal of deposited A-Beta in amyloid plaques, in case of imbalance and disease.…”

Alterations in immunological and neurological gene expression patterns in Alzheimer's disease tissues

“…Only two reports to date have implicated ECEs in the clearance of β-amyloid in vitro [19] and in animal models [20], but no laboratory has demonstrated the loss of ECE mRNA or protein expression in human AD tissue. In our current report, we demonstrate that the ECE family member ECE2 is significantly lost in AD, but not in other types of dementia, suggesting that this is not merely a side-effect of neurodegeneration, but a specific AD-related event.…”

“…ECE2 is an endothelin converting enzyme responsible for the degradation of amyloid beta [19,20]. ECEs are important in Aβ clearance, and mice deficient in ECE1 have increased steady state levels of Aβ [20].…”

Somatostatin and Alzheimer's disease

“…A c c e p t e d M a n u s c r i p t 11 Several zinc metallopeptidases have been recently identified as A-degrading enzymes; these include neprilysin (Iwata et al, 2000;Iwata et al, 2001), endothelin-converting enzyme (Eckman et al, 2001), and insulin-degrading enzyme .…”