Aβ-degrading enzymes:: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention

The accumulation of A beta (amyloid beta-protein) peptides in the brain is a pathological hallmark of all forms of AD (Alzheimer's disease) and reducing A beta levels can prevent or reverse cognitive deficits in mouse models of the disease. A beta is produced continuously and its concentration is determined in part by the activities of several degradative enzymes, including NEP (neprilysin), IDE (insulin-degrading enzyme), ECE-1 (endothelin-converting enzyme 1) and ECE-2, and probably plasmin. Decreased activity of any of these enzymes due to genetic mutation, or age- or disease-related alterations in gene expression or proteolytic activity, may increase the risk for AD. Conversely, increased expression of these enzymes may confer a protective effect. Increasing A beta degradation through gene therapy, transcriptional activation or even pharmacological activation of the A beta-degrading enzymes represents a novel therapeutic strategy for the treatment of AD that is currently being evaluated in cell-culture and animal models. in this paper, we will review the roles of NEP, IDE, ECE and plasmin in determining endogenous A beta concentration, highlighting recent results concerning the regulation of these enzymes and their potential as therapeutic targets.