Nature Neuroscience5, 849 - 855 (2002)
Published online: 29 July 2002; | doi:10.1038/nn898
Presenilins are not required for A42 production in the early secretory pathway
Christina A. Wilson1, Robert W. Doms1, 2, Hui Zheng3, 4
& Virginia M.-Y. Lee1
1
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
2
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
3
Merck Research Laboratories, PO Box 2000, Rahway, New Jersey 07065, USA
4
Present address: Huffington Center on Aging, Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
Presenilins 1 and 2 (PS1/PS2) have been suggested to be -secretases responsible for the proteolytic cleavage of amyloid precursor protein (APP) to form amyloid- (A), a protein implicated in the development of Alzheimer's disease. Here we examined whether these presenilins are required for the generation of multiple A species by analyzing the production of several forms of secreted and intracellular A in mouse cells lacking PS1, PS2 or both proteins. Although most A species were abolished in PS1/PS2-/- cells, the production of intracellular A42 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 A occurs independently of PS1/PS2, and therefore, another -secretase activity must be responsible for cleavage of APP within the early secretory compartments.
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