The abnormal accumulation of -amyloid (A) 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. As with any peptide, however, the degree of A 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-degrading enzyme that appears to act intracellularly, thus limiting the amount of A available for secretion. To determine the physiological significance of this activity, we analyzed A levels in the brains of mice deficient for ECE-1 and a closely related enzyme, ECE-2. Significant increases in the levels of both A40 and A42 were found in the brains of these animals when compared with age-matched littermate controls. The increase in A 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 accumulation in the brain and also provides further insight into the factors involved in A clearance in vivo.Alzheimer's disease (AD), 1 the most common cause of dementia in the elderly, is characterized pathologically by the accumulation of -amyloid peptides (A40 and A42) in the brain. Although considerable attention has been focused on understanding the enzymes and processes involved in the production of A, very little is known regarding the processes by which A is normally removed. This removal can be in the form of transport of the peptide into the cerebrospinal fluid for peripheral clearance, by binding to proteins that sequester the peptide in a nonreactive form, or by direct catabolism of A. A significant role for A catabolism has been highlighted in a recent report by Saido and colleagues (1) in which they showed that infusion of the metalloprotease inhibitor thiorphan into the hippocampus of rats resulted in localized A deposition, reportedly through the inhibition of A degradation by neprilysin (NEP).A catabolism appears complex. Recent reports suggest significant roles for insulin-degrading enzyme, NEP, and the plasmin system in the catabolism of A (1-10). Angiotensin-converting enzyme, matrix metalloproteinase-9, EC 3.4.24.15, and ␣-2 macroglobulin complexes have also been reported to play a role in A degradation on the basis of in vitro and cell-based assays (11)(12)(13)(14). To date, however, only neprilysin has been reported to influence A levels in the brains of knock-out mice (1,5,15).Using pharmacological, molecular, and biochemical approaches, we have previously characterized endothelin-converting enzyme-1 (ECE-1) as a novel A-degrading enzyme that appears to act intracellularly to reduce the amount of A available for secretion (16). Overexpression of ECE-1 in cells that lack endogenous ECE activity results in a pronounced decrease in A accumulation in the...
Alzheimer's disease (AD) is the most common form of dementia in the elderly. Without a treatment that significantly delays the progression of the disease over 14 million Americans are likely to be affected with AD by the middle of the 21st Century, presenting an enormous economic and social burden. Evidence gathered over the last two decades has implicated the abnormal accumulation of A beta, in particular the longer more amyloidogenic form A beta42, as a potential causative agent in the disease. To screen for compounds that reduce A beta accumulation we have established several high throughput, cell based screens capable of the sensitive and selective detection of A beta40 and A beta42. Using these screens we have analyzed a proprietary library of natural product extracts for their ability to influence A beta accumulation. Using this approach, we have identified several agents capable of influencing total A beta concentration. In addition, we have identified one extract that selectively reduces A beta42. Intracerebroventricular administration of this agent to mice results in a selective reduction in A beta42 in the brain.
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