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¹ Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, 80336 Munich, Germany
² Advanced Light Microscopy Facility, European Molecular Biology Laboratories, 69012 Heidelberg, Germany

Address correspondence to Christian Haass, Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, Munich, Schillerstrasse 44, 80336 Munich, Germany. Tel.: 49-89-5996-471/472. Fax: 49-89-5996-415. E-mail: chaass{at}pbm.med.uni-muenchen.de

Amyloid ß-peptide (Aß) is generated by the consecutive cleavages of ß- and -secretase. The intramembraneous -secretase cleavage critically depends on the activity of presenilins (PS1 and PS2). Although there is evidence that PSs are aspartyl proteases with -secretase activity, it remains controversial whether their subcellular localization overlaps with the cellular sites of Aß production. We now demonstrate that biologically active GFP-tagged PS1 as well as endogenous PS1 are targeted to the plasma membrane (PM) of living cells. On the way to the PM, PS1 binds to nicastrin (Nct), an essential component of the -secretase complex. This complex is targeted through the secretory pathway where PS1-bound Nct becomes endoglycosidase H resistant. Moreover, surface-biotinylated Nct can be coimmunoprecipitated with PS1 antibodies, demonstrating that this complex is located to cellular sites with -secretase activity. Inactivating PS1 or PS2 function by mutagenesis of one of the critical aspartate residues or by -secretase inhibitors results in delayed reinternalization of the ß-amyloid precursor protein and its accumulation at the cell surface. Our data suggest that PS is targeted as a biologically active complex with Nct through the secretory pathway to the cell surface and suggest a dual function of PS in -secretase processing and in trafficking.

Key Words: Alzheimer's disease; presenilin; GFP; nicastrin; amyloid precursor protein

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