Neprilysin protects human neuronal progenitor cells against impaired development caused by amyloid-beta peptide

Transplantation of human neuronal progenitor cells (HNPC) is being considered for neuroreplacement therapy in beta-amyloidosis associated with neuronal loss in Down's syndrome and Alzheimer's disease. However, the influence of amyloid-beta-containing brain environment on the development of HNPCs is unknown. Recently, we demonstrated that amyloid-beta peptide (Abeta) impaired differentiation of HNPCs in culture through oxidative stress. Now we studied the effect of neprilysin, an Abeta-degrading enzyme, on development of neuronal colonies from neurospheres of HNPCs in the presence of Abeta1-40. Neprilysin increased the number of neurospheres that formed colonies of neuron-like cells. This effect of neprilysin was associated with reduced amounts of the monomeric and dimeric Abeta that remained in culture supernatants as well as the Abeta uptaken by differentiating HNPCs. Phosphoramidon, a neprilysin inhibitor, attenuated these effects of neprilysin. In control cultures of HNPCs that grew without exogenous Abeta1-40, the treatment with neprilysin reduced the number of developing colonies. This effect might result from degradation by neprilysin of endogenous Abeta produced and secreted by HNPCs or other peptides that are involved in neuronal development. The results demonstrate that even a partial reduction of extracellular Abeta levels by neprilysin may facilitate development of HNPCs into neurons in an environment overloaded with Abeta. This finding suggests that neprilysin could facilitate neuroreplacement therapy with HNPCs in treatment of neurodegenerative diseases.