ABSTRACT
Amyloid ß peptide (Aß), the pathogenic agent of Alzheimer’s disease (AD), is a physiological metabolite in the brain. We focused our attention and effort on elucidation of the unresolved aspect of Aß metabolism, proteolytic degradation. Among a number of Aß-degrading enzyme candidates, we identified a member of the neutral endopeptidase family, neprilysin, as the major catabolic enzyme using a novel in vivo paradigm. Consistently, neprilysin deficiency resulted in defects in the metabolism of endogenous Aß 40 and 42, notably, in a gene dose-dependent manner. Our observations suggest that even partial down-regulation of neprilysin activity, which could be caused by aging, can contribute to AD development by promoting Aß accumulation. Moreover, we describe that an aging-dependent decline of neprilysin activity, leading to elevation of Aß levels in the brain is a natural process preceding AD pathology. We not only hypothesize in this chapter on the likely role of neprilysin down-regulation in sporadic AD (SAD) pathogenesis but also propose that the knowledge itself be used for developing novel preventive and therapeutic strategies. Finally, we also discuss the need for mathematical refinement of the current human genetic approaches to identify the risk and anti-risk factors for AD.
