rane and/or to late compartments 22277057 of the secretory pathway. In addition to its proteolytic activity, presenilin also exhibits a low, but functionally significant conductance for Ca2+ in the endoplasmic reticulum, and many familial AD-associated presenilin mutations impair this function, indicating that presenilin functions as passive low conductance Ca2+ channel. In the immature c-secretase complex, presenilin forms a hydrophilic catalytic pore with an open conformational structure, while it adopts a conformation in the mature functional c-secretase complex that forms a water-filled pore which provides the microenvironment for intramembranous cleavage of proteins. Of particular importance for formation of such catalytic pore are the transmembrane domains TMD1, -7 and -9 of presenilin. Calreticulin is a ubiquitously expressed soluble MedChemExpress PBTZ 169 protein that displays multiple functions not only in intracellular compartments, such as the ER, cytoplasm and nucleus, but also in the extracellular space. Its biological importance is revealed by embryonic lethality in mice when the calreticulin gene is ablated. In the lumen of the ER, calreticulin functions as chaperone that is involved in protein quality control by elimination of proteins with improper folding, thus ensuring trafficking of proteins with proper folding and preventing protein aggregation. Calreticulin controls also metabolic and homeostatic Ca2+ levels in the cytosol and ER. Extracellular calreticulin, also called ecto-calreticulin, regulates diverse cellular activities, 
such as antigen processing and presentation, phagocytosis of apoptotic and cancer cells as well as cell adhesion, migration and proliferation. These different findings indicate that extracellular calreticulin regulates a multitude of physiological functions and underscore its critical impact in pathology when it is prevented to function normally. It is noteworthy in this context that calreticulin is 23237488 found in a complex with APP and Ab and that levels of the calreticulin mRNA and protein are reduced in patients with AD, suggesting that calreticulin is implicated also in the proteolytic processing of APP and, thus, in AD pathogenesis. Since calreticulin binds to APP and Ab, it is conceivable that calreticulin not only interacts with APP in intracellular compartments, but also at the plasma membrane and/or in extracellular compartments. Here, we provide evidence that calreticulin interacts with APP and presenilin at the cell surface and that this interaction of calreticulin reduces the generation of Ab. antibody were described. Rabbit monoclonal antibody `Nixon and rabbit polyclonal antibody 2953 against presenilin-1 as well as the rabbit polyclonal antibody N1660 raised against the C-terminus of nicastrin and the rabbit polyclonal 2D8 antibody directed against Ab were kindly provided by Harald Steiner. Secondary antibodies and control antibodies were from Dianova. Synthetic biotinylated APP-c and APP-b peptides as well as the calreticulin peptide were from Schafer-N. Antisense peptide NH2-QGDDDHCRYDNTAHHOH was synthesized by Chirion Technologies or Schafer-N. Recombinant calreticulin proteins and calreticulin cDNA constructs Recombinant rabbit calreticulin as well as glutathione Stransferase fusion proteins comprising full-length calreticulin or calreticulin domains N and P, P or C were prepared as previously described. The cDNA encoding full-length rabbit calreticulin, the N-domain, the P-domain, or the N- and P-domains of ca