Alzheimer's Disease [beta]-Amyloid Peptide Is Increased in Mice Deficient in Endothelin-converting Enzyme

The abnormal accumulation of [beta]-amyloid (A[beta]) in the brain is an early and invariant feature in Alzheimer's disease (AD) and is believed to play a pivotal role in the etiology and pathogenesis of the disease. As such, a major focus of AD research has been the elucidation of the mechanisms responsible for the generation of A[beta]. As with any peptide, however, the degree of A[beta] accumulation is dependent not only on its production but also on its removal. In cell-based and in vitro models we have previously characterized endothelin-converting enzyme-1 (ECE-1) as an A[beta]-degrading enzyme that appears to act intracellularly, thus limiting the amount of A[beta] available for secretion. To determine the physiological significance of this activity, we analyzed A[beta] levels in the brains of mice deficient for ECE-1 and a closely related enzyme, ECE-2. Significant increases in the levels of both A[beta]40 and A[beta]42 were found in the brains of these animals when compared with age-matched littermate controls. The increase in A[beta] levels in the ECE-deficient mice provides the first direct evidence for a physiological role for both ECE-1 and ECE-2 in limiting A[beta] accumulation in the brain and also provides further insight into the factors involved in A[beta] clearance in vivo.