That neprilysin (NEP) is a major Abeta peptide-degrading enzyme in vivo is shown by higher Abeta peptide levels in the brain of an NEP knockout mouse. In addition, we show that infusion of an NEPinhibitor, but not inhibitors of other peptidases, into the brains of an APP transgenic mouse elevates Abeta levels. We have investigated the use of NEP as a potential therapeutic agent to prevent the accumulation of Abeta peptides in the brain. Lentivirus expressing NEP was initially used to demonstrate the ability of the enzyme to reduce Abeta levels in a model CHO cell line and to make primary hippocampal neurons resistant to Abeta-mediated neurotoxicity. Injection of NEPexpressing lentivirus, but not inactive NEP-expressing lentivirus, GFP-expressing lentivirus, or vehicle, into the hippocampus of 12-20-mo-old hAPP transgenic mice led to an approx 50% reduction in the number of amyloid plaques. These studies provide the impetus for further investigating of the use of NEP in a gene transfer therapy paradigm to prevent the accumulation of Abeta and prevent or delay the onset of Alzheimer's disease.