Proteolytic processing of P-amyloid precursor protein (APP) is believed to be fundamental to the understanding of Alzheimer's disease. The identities and the regulatory elements of the proteases involved in the process, known as alpha/beta/gamma secretases, are unclear. In this study, by examining reported data, we found some indications suggesting that the putative alpha-secretase may be a calcium-dependent protease, and that this enzyme may play a primary role in the regulation of APP processing. Based on this, we proposed a model for the membrane orientations of the secretases for further discussions, (C) 1997 Federation of European Biochemical Societies.