The amyloid-42 (A42) peptide has been suggested to play a causative role in Alzheimer’s disease (AD). Neprilysin (NEP) is one of the rate-limiting A-degrading enzymes whose genetic deficiencies promote increased A levels in the brain. Enhancement of NEP activity ameliorates extracellular amyloid pathology, synaptic dysfunction, and memory defects in mouse models of A amyloidosis, suggesting that NEP is an attractive therapeutic target for AD. In addition to accumulation in the extracellular space, intraneuronal A42 may contribute to AD pathogenesis. However, the effects of neuronal NEP expression on intraneuronal Aß42 accumulation and neurodegeneration in the brain remain elusive. In addition, sustained NEP activation in neurons may be detrimental because NEP can degrade many physiological peptides, but the consequences of chronic NEP expression in the brain are not fully understood. Using transgenic Drosophila expressing human NEP and A42, we demonstrated that NEP efficiently degraded A42 expressed in the secretory pathway of neurons, suppressed the formation of intraneuronal TS-positive A42 deposits, and reduced A42-induced neuron loss. However, neuronal NEP overexpression reduced CREB-mediated transcription, caused age-dependent axon degeneration and shortened lifespan of the flies. Interestingly, the mRNA levels of endogenous fly NEP genes and phosphoramidon-sensitive NEP activity declined during aging in fly brains, as observed in mammals. Taken together, these data suggest both protective and detrimental effects of chronically high NEP activity in the brain. Downregulation of mRNA levels and activity of NEP in aging brains may be an evolutionarily conserved phenomenon, which could predispose humans to developing late-onset AD.