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J. Biol. Chem., Vol. 279, Issue 39, 40560-40566, September 24, 2004

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Presenilins and -Secretase Inhibitors Affect Intracellular Trafficking and Cell Surface Localization of the -Secretase Complex Components^*

Hong Wang, Wen-jie Luo, Yun-wu Zhang¶, Yue-Ming Li||, Gopal Thinakaran**, Paul Greengard, and Huaxi Xu¶

From the The Fisher Center for Alzheimer's Disease Research and the Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, ^¶Center for Neuroscience and Aging, The Burnham Institute, La Jolla, California 92037, ^||Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and ^**Department of Neurobiology, Pharmacology, and Physiology, The University of Chicago, Chicago, Illinois 60637

The intramembranous cleavage of Alzheimer -amyloid precursor protein and the signaling receptor Notch is mediated by the presenilin (PS, PS1/PS2)--secretase complex, the components of which also include nicastrin, APH-1, and PEN-2. In addition to its essential role in -secretase activity, we and others have reported that PS1 plays a role in intracellular trafficking of select membrane proteins including nicastrin. Here we examined the fate of PEN-2 in the absence of PS expression or -secretase activity. We found that PEN-2 is retained in the endoplasmic reticulum and has a much shorter half-life in PS-deficient cells than in wild type cells, suggesting that PSs are required for maintaining the stability and proper subcellular trafficking of PEN-2. However, the function of PS in PEN-2 trafficking is distinct from its contribution to -secretase activity because inhibition of -secretase activity by -secretase inhibitors did not affect the PEN-2 level or its egress from the endoplasmic reticulum. Instead, membrane-permeable -secretase inhibitors, but not a membrane-impermeable derivative, markedly increased the cell surface levels of PS1 and PEN-2 without affecting that of nicastrin. In support of its role in PEN-2 trafficking, PS1 was also required for the -secretase inhibitor-induced plasma membrane accumulation of PEN-2. We further showed that -secretase inhibitors specifically accelerated the Golgi to the cell surface transport of PS1 and PEN-2. Taken together, we demonstrate an essential role for PSs in intracellular trafficking of the -secretase components, and that selective -secretase inhibitors differentially affect the trafficking of the -secretase components, which may contribute to an inactivation of -secretase.

Received for publication, April 20, 2004 , and in revised form, June 24, 2004.

^* This work is supported in part by National Institutes of Health Grants AG09464 (to P. G. and H. X.), NS046673 (to H. X.), F32 AG023432-01 (to W. L.), and AG021495 (to G. T.) and by a grant from the Alzheimer's Association (to H. X.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 858-713-9946; Fax: 858-713-6273; E-mail: xuh{at}burnham.org.

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