Distinct presenilin-dependent and presenilin-independent γ-secretases are responsible for total cellular Aβ production

gamma-Secretase is the second of two proteolytic enzymes involved in the liberation of the beta-amyloid peptide (AP) from the amyloid precursor protein (APP). gamma-Secretase cleavage occurs at several intracellular sites, including the Golgi network and the endoplasmic reticulum/ intermediate compartment (ER/IC) to produce multiple forms of the Abeta peptide that can be either secreted from the cell or remain intracellular. To date, most evidence has suggested that members of the presenilin protein family are required for gamma-secretase activity. Although it seems that presenilins are indeed necessary for the production of most secreted and intracellular Abeta particularly that generated in downstream organelles, it was shown recently that a presenilin-independent gamma-secretase is active in the ER/IC and is responsible for the production of a portion of intracellular Abeta42. We discuss the implications of this finding for the understanding of presenilin biology and speculate on the putative identity of the presenilin-independent cleavage activity. (C) 2003 Wiley-Liss, Inc.