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 gen
eration of A beta, Much less, however, is known about the mechanisms respon
sible for A beta removal in the brain, In this report, we describe the iden
tification of endothelin-converting enzyme-1 (ECE-1) as a novel A beta -deg
rading enzyme. We show that treatment of endogenous ECE-expressing cell lin
es with the metalloprotease inhibitor phosphoramidon causes a 2-3-fold elev
ation in extracellular A beta concentration that appears to be due to inhib
ition of intracellular A beta degradation. Furthermore, we show that overex
pression 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 phosphor
amidon. Finally, we show that recombinant soluble ECE-1 is capable of hydro
lyzing synthetic A beta 40 and A beta 42 in vitro at multiple sites.