Degradation of the Alzheimer's amyloid β peptide by endothelin-converting enzyme

Deposition of beta -amyloid (A beta) 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 beta 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 beta, Much less, however, is known about the mechanisms responsible for A beta removal in the brain, In this report, we describe the identification of endothelin-converting enzyme-1 (ECE-1) as a novel A beta -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 beta concentration that appears to be due to inhibition of intracellular A beta degradation. Furthermore, we show that overexpression of ECE-1 in Chinese hamster ovary cells, which lack endogenous ECE activity, reduces extracellular A beta 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 beta 40 and A beta 42 in vitro at multiple sites.