Presenilins are not required for Aβ42 production in the early secretory pathway

Presenilins 1 and 2 (PS1/PS2) have been suggested to be gamma-secretases responsible for the proteolytic cleavage of amyloid precursor protein (APP) to form amyloid-beta (Abeta), a protein implicated in the development of Alzheimer's disease. Here we examined whether these presenilins are required for the generation of multiple Abeta species by analyzing the production of several forms of secreted and intracellular Abeta in mouse cells lacking PS1, PS2 or both proteins. Although most Abeta species were abolished in PS1/PS2(-/-) cells, the production of intracellular Abeta42 generated in the endoplasmic reticulum/intermediate compartment was unaffected by the absence of these proteins, either singly or in combination. These results indicate that production of this pool of Abeta occurs independently of PS1/PS2, and therefore, another gamma-secretase activity must be responsible for cleavage of APP within the early secretory compartments.