Diabetes NEP-Like Endopeptidases and Alzheimer's Disease

The accumulation of the amyloid-beta peptide (A beta) continues to emerge as a central factor in Alzheimer's disease (AD). In recent years attention has been drawn to clearance mechanisms of A beta as evidence suggests reduced clearance may be linked to late-onset AD. Direct degradation of A beta by endopeptidases has emerged as one critical pathway of clearance. Of particular interest are endopeptidases that are sensitive to the neprilysin inhibitors thiorphan and phosphoramidon (i.e. NEP-like)as these inhibitors induce a dramatic increase in A beta levels resulting in rapid plaque formation in wild-type rodents. This review focuses on neprilysin (NEP) and on another NEP-like endopeptidase termed neprilysin-2 (NEP2). The involvement of these endopeptidases in AD and the state of their therapeutic development are discussed.