To investigate the induction of 'a disintegrin and metalloprotease' 9 (ADAM9) by which estrogen receptor (ER) subtypes and estrogen regulation of expression in cultured human neuronal cells.SH-SY5Y cells were treated with E2 and the expression of ADAM9 were detected by RT-PCR and Western blot analysis. The peGFP-C3-ERα and peGFP-C3-ERβ vectors were constructed and transfected into SH-SY5Y cells. Then, the mRNA and protein expression level of ADAM9 were detected by RT-PCR and Western blot analyses with the treatment of E2. E2, the ERα agonist PPT, the ERβ agonist DPN and the non-specific ER antagonist ICI 182,780 were added, and the expression of ADAM9 protein and transcriptional activities of ADAM9 promoter were detected by Western blot and luciferase assays, respectively.E2 induced ADAM9 expression with a time-dependent manner in SHSY5Y cells, reaching the peak at 24h. peGFP-C3-ERα transfection significantly increased ADAM9 expression in the presence of E2, whereas peGFP-C3-ERβ had no effect. The E2-induced overexpression of ADAM9 protein was downregulated by ICI 182,780. PPT significantly increased ADAM9 protein expression, whereas DPN had no effect. The E2-induced increase in the transcriptional activities of the ADAM9 promoter was downregulated by ICI 182,780. PPT significantly increased the transcriptional activities of the ADAM9 promoter, whereas DPN had no effect.Activation of ERα but not ERβ increases ADAM9 expression in cultured human neuronal cells, implicating that ERα-activation functions in the direct mechanism underlying the estrogen-mediated preventative effects against Aβ production and further reduction in the risk of Alzheimer's disease.