The abnormal accumulation of beta-amyloid (Abeta) in the brain is believed to play a pivotal role in the etiology and pathogenesis of Alzheimer's disease. As such, a major focus of AD research has been the elucidation of the mechanisms responsible for the generation of Abeta. As with any peptide, however, the degree of Abeta 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 Abeta-degrading enzyme that appears to act intracellularly, thus limiting the amount of Abeta available for secretion. To determine the physiological significance of this activity we have analyzed Abeta levels in the brains of mice deficient for ECE-1 and a closely related enzyme, ECE-2. Significant increases in the levels of both Abeta40 and Abeta42 were found in the brains these animals when compared to age matched, littermate controls. These data provide strong support for our working hypothesis that ECE activity limits Abeta accumulation in the brain. In this application we propose to further test this hypothesis and to determine whether these elevations in Abeta levels will result in deposition or an enhancement of deposition in mouse models. Additionally we propose to extend our analysis into human brain. Given the evidence that Abeta plays a significant role in AD pathogenesis, understanding those factors that can influence Abeta levels, such as ECE activity, may provide new insights into the disease and could provide novel therapeutic approaches. Equally important, ECE inhibitors are being developed as novel anti-hypertensives. Understanding the effects of chronic reductions in ECE activity has the additional advantage that it may shed light on a significant potential side effect of the use of these drugs that may not be observed in normal clinical trials.
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