Amino-terminal region of secreted form of amyloid precursor protein stimulates proliferation of neural stem cells

beta-Amyloid precursor protein (APP) has been reported to be expressed in t he CNS from the early stages of development. However, the functional role o f APP during early development remains unclear. In the present study, we fo und that the secreted form of APP (sAPP) significantly enhanced proliferati on of neural stem cells. Cells were prepared from 13-day embryonic rat neoc ortex, which was dissected with a Pasteur pipette to make cell clusters. Af ter 12 h of cultivation in the medium without serum, cells around the centr e of the cluster were still nestin-positive proliferative cells, i.e. neura l stem cells. To determine whether the proliferation of cells was regulated by sAPP, cultures were treated with recombinant sAPP695, the secreted form of human APP695 produced by yeast. Both DNA synthesis and expression of pr oliferating cell nuclear antigen markedly increased after 5 h of sAPP695 ad dition. The enhancement of DNA synthesis by sAPP695 stimulation was blocked by the 22C11 monoclonal antibody specific for the amino-terminal region of sAPP. Then, we examined the effect of the amino-terminal fragment of sAPP and the epitope peptide of 22C11 antibody, and found that both of them also promoted DNA synthesis, suggesting that the amino-terminal region of sAPP is responsible for the biological activity. Our findings indicate the possi bility that sAPP enhances proliferation of neural stem cells in vivo and pl ays an important role during the early CNS development.