Amyloid-beta and Alzheimer's disease: the role of neprilysin-2 in amyloid-beta clearance

Accumulation of the amyloid-beta (A beta) peptide is a central factor in Alzheimer's disease (AD) pathogenesis as supported by continuing evidence. This review concisely summarizes this evidence supporting a critical role for A beta in AD before discussing the clearance of this peptide. Mechanisms of clearance of A beta are critical for preventing pathological elevations in A beta concentration. Direct degradation of A beta by endopeptidases has emerged as one important pathway for clearance. Of particular interest are endopeptidases that are sensitive to the neprilysin (NEP) inhibitors thiorphan and phosphoramidon (i.e., are NEP-like) as these inhibitors induce a dramatic increase in A beta levels in rodents. This review will focus on neprilysin-2 (NEP2), a NEP-like endopeptidase which cooperates with NEP to control A beta levels in the brain. The evidence for the involvement of NEP2 in AD is discussed as well as the therapeutic relevance with regards to gene therapy and the development of molecular markers for the disease.