ADAM9 (MDC9, meltrin gamma) is a member of the ADAM family of metalloproteases, which play important roles in cell-cell fusion. intracellular signaling, and other cellular functions. Here we cloned a novel form of human ADAM9, designated hADAM9s (s for short), which lacks the carboxyl-terminus. Human ADAM9s was found to be secreted from transfected COS cells. RT-PCR analysis demonstrated that the mRNA for hADAM9s is expressed in human brain, liver, heart. kidney, lung, and trachea. When hADAM9s was co-expressed in COS cells with APP and treated with phorbol ester. the APP was digested exclusively at the alpha-secretory site. These results suggest that hADAM9s has an alpha-secretase-like activity for APP. Non-amyloidgenic cleavage of APP may occur at the plasma membrane. Our new results support a new therapeutic strategy to decrease in the AP content by directly activating ADAM9 in the extracellular space. (C) 2002 Elsevier Science (USA). All rights reserved.