We have investigated the effect of the Alzheimer amyloid protein precursor (APP) on the proliferation of neural stem cells. Two secretory forms of APP (sAPP770 and sAPP695, with and without the Kunitz-type serine protease inhibitor domain, respectively) were purified from conditioned media of COS-7 cells transfected with genetically modified APP cDNAs. Both secretory APPs promoted the growth of neural stem cells, and the effect of sAPP770 was greater than that of sAPP695. sAPP770 and known growth factors in combination exerted a cooperative stimulation of the stem cell proliferation. These results suggest that APP, especially APP possessing the protease inhibitor domain, regulates the growth of neuronal precursor cells during development of the nervous system.