Constitutive α-secretase cleavage of the β-amyloid precursor protein in the furin-deficient LoVo cell line:: involvement of the pro-hormone convertase 7 and the disintegrin metalloprotease ADAM10

The beta -amyloid precursor protein (beta APP) undergoes a physiological cleavage triggered by one or several proteolytic activities referred to as alpha -secretases, leading to the secretion of sAPP alpha. Several lines of evidence indicate that the alpha -secretase cleavage is a highly regulated process. Thus, besides constitutive production of sAPPa, several studies have reported on protein kinase C-regulated sAPP alpha secretion. Studies aimed at identifying alpha -secretase(s) candidates suggest the involvement of enzymes belonging to the prohormone convertases and disintegrin families. The delineation of respective contributions of proteolytic activities in constitutive and regulated sAPPa secretion is rendered difficult by the fact that the overall regulated response always includes the basal constitutive counterpart that cannot be selectively abolished. Here we report on the fact that the furin-deficient LoVo cells are devoid of regulated PKC-dependent sAPP alpha secretion and therefore represent an interesting model to study exclusively the constitutive sAPP alpha secretion. We show here, by a pharmacological approach using selective inhibitors, that pro-hormone convertases and proteases of the ADAM (disintegrin metalloproteases) family participate in the production/secretion of sAPP alphas in LoVo cells. Transfection analysis allowed us to further establish that the pro-hormone convertase 7 and ADAM10 but not ADAM17 (TACE, tumour necrosis factor cu-converting enzyme) likely contribute to constitutive sAPP alpha secretion by LoVo cells.