The cellular prion protein (PrP (C) ) is subjected to various processing under physiological and pathological conditions, of which the α-cleavage within the central hydrophobic domain not only disrupts a region critical for both PrP toxicity and PrP (C) to PrP (Sc) conversion but also produces the N1 fragment that is neuroprotective and the C1 fragment that enhances the pro-apoptotic effect of staurosporine in one report and inhibits prion in another. The proteases responsible for the α-cleavage of PrP (C) are controversial. The effect of ADAM10, ADAM17, and ADAM9 on N1 secretion clearly indicates their involvement in the α-cleavage of PrP (C) , but there has been no report of direct PrP (C) α-cleavage activity with any of the three ADAMs in a purified protein form. We demonstrated that, in muscle cells, ADAM8 is the primary protease for the α-cleavage of PrP (C) , but another unidentified protease(s) must also play a minor role. We also found that PrP (C) regulates ADAM8 expression, suggesting that a close examination on the relationships between PrP (C) and its processing enzymes may reveal novel roles and underlying mechanisms for PrP (C) in non-prion diseases such as asthma and cancer.