Journal of Cell Science, Vol 109, Issue 5 991-998, Copyright © 1996 by Company of Biologists

JOURNAL ARTICLES

Trafficking of cell-surface amyloid beta-protein precursor. I. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody

EH Koo, SL Squazzo, DJ Selkoe and CH Koo
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.

Amyloid beta-protein, the principal constituent of amyloid fibrils found in senile plaques and blood vessels in Alzheimer's disease, is constitutively produced and released into medium of cultured cells. Amyloid beta-protein is derived by proteolysis of the beta-amyloid precursor protein by unclear mechanisms. Beta-amyloid precursor protein is a transmembrane protein which can be processed to release a large secretory product or processed in the endosomal/lysosomal pathway without secretion. Previous studies have shown that from the cell surface, beta-amyloid precursor protein may be released after cleavage or internalized without cleavage, the latter in a pathway that both produces amyloid beta-protein and also targets some molecules to the lysosomal compartment. Analysis of beta-amyloid precursor protein trafficking is confounded by the concomitant secretion and internalization of molecules from the cell surface. To address this issue, we developed an assay, based on the binding of radioiodinated monoclonal antibody, to measure the release and internalization of cell surface beta-amyloid precursor protein in transfected cells. With this approach, we showed that surface beta-amyloid precursor protein is either rapidly released or internalized, such that the duration at the cell surface is very short. Approximately 30% of cell surface beta-amyloid precursor protein molecules are released. Following internalization, a fraction of molecules are recycled while the majority of molecules are rapidly sorted to the lysosomal compartment for degradation When the C terminus of beta-amyloid precursor protein is deleted, secretion is increased by approximately 2.5-fold as compared to wild-type molecules. There is concomitant decrease in internalization in these mutant molecules as well as prolongation of the resident time on the cell surface. This observation is consistent with recent evidence that signals within the cytoplasmic domain mediate beta-amyloid precursor protein internalization.

This article has been cited by other articles:

				C. R. Burton, J. E. Meredith, D. M. Barten, M. E. Goldstein, C. M. Krause, C. J. Kieras, L. Sisk, L. G. Iben, C. Polson, M. W. Thompson, et al. The Amyloid-{beta} Rise and {gamma}-Secretase Inhibitor Potency Depend on the Level of Substrate Expression J. Biol. Chem., August 22, 2008; 283(34): 22992 - 23003. [Abstract] [Full Text] [PDF]

				J. Lee, C. Retamal, L. Cuitino, A. Caruano-Yzermans, J.-E. Shin, P. van Kerkhof, M.-P. Marzolo, and G. Bu Adaptor Protein Sorting Nexin 17 Regulates Amyloid Precursor Protein Trafficking and Processing in the Early Endosomes J. Biol. Chem., April 25, 2008; 283(17): 11501 - 11508. [Abstract] [Full Text] [PDF]

				A. Schneider, L. Rajendran, M. Honsho, M. Gralle, G. Donnert, F. Wouters, S. W. Hell, and M. Simons Flotillin-Dependent Clustering of the Amyloid Precursor Protein Regulates Its Endocytosis and Amyloidogenic Processing in Neurons J. Neurosci., March 12, 2008; 28(11): 2874 - 2882. [Abstract] [Full Text] [PDF]

				I.-S. Yoon, E. Chen, T. Busse, E. Repetto, M. K. Lakshmana, E. H. Koo, and D. E. Kang Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway FASEB J, September 1, 2007; 21(11): 2742 - 2752. [Abstract] [Full Text] [PDF]

				D. Tampellini, J. Magrane, R. H. Takahashi, F. Li, M. T. Lin, C. G. Almeida, and G. K. Gouras Internalized Antibodies to the Abeta Domain of APP Reduce Neuronal Abeta and Protect against Synaptic Alterations J. Biol. Chem., June 29, 2007; 282(26): 18895 - 18906. [Abstract] [Full Text] [PDF]

				N. N. Dewji, D. Mukhopadhyay, and S. J. Singer An early specific cell-cell interaction occurs in the production of beta-amyloid in cell cultures PNAS, January 31, 2006; 103(5): 1540 - 1545. [Abstract] [Full Text] [PDF]

				R. Spoelgen, C. A. F. von Arnim, A. V. Thomas, I. D. Peltan, M. Koker, A. Deng, M. C. Irizarry, O. M. Andersen, T. E. Willnow, and B. T. Hyman Interaction of the Cytosolic Domains of sorLA/LR11 with the Amyloid Precursor Protein (APP) and beta-Secretase beta-Site APP-Cleaving Enzyme J. Neurosci., January 11, 2006; 26(2): 418 - 428. [Abstract] [Full Text] [PDF]

				S. Ye, Y. Huang, K. Mullendorff, L. Dong, G. Giedt, E. C. Meng, F. E. Cohen, I. D. Kuntz, K. H. Weisgraber, and R. W. Mahley Apolipoprotein (apo) E4 enhances amyloid {beta} peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target PNAS, December 20, 2005; 102(51): 18700 - 18705. [Abstract] [Full Text] [PDF]

				I. Y. Tamboli, K. Prager, E. Barth, M. Heneka, K. Sandhoff, and J. Walter Inhibition of Glycosphingolipid Biosynthesis Reduces Secretion of the {beta}-Amyloid Precursor Protein and Amyloid {beta}-Peptide J. Biol. Chem., July 29, 2005; 280(30): 28110 - 28117. [Abstract] [Full Text] [PDF]

				I.-S. Yoon, C. U. Pietrzik, D. E. Kang, and E. H. Koo Sequences from the Low Density Lipoprotein Receptor-related Protein (LRP) Cytoplasmic Domain Enhance Amyloid {beta} Protein Production via the {beta}-Secretase Pathway without Altering Amyloid Precursor Protein/LRP Nuclear Signaling J. Biol. Chem., May 20, 2005; 280(20): 20140 - 20147. [Abstract] [Full Text] [PDF]

				J. A. Cam, C. V. Zerbinatti, Y. Li, and G. Bu Rapid Endocytosis of the Low Density Lipoprotein Receptor-related Protein Modulates Cell Surface Distribution and Processing of the {beta}-Amyloid Precursor Protein J. Biol. Chem., April 15, 2005; 280(15): 15464 - 15470. [Abstract] [Full Text] [PDF]

				J. H. Chyung, D. M. Raper, and D. J. Selkoe {gamma}-Secretase Exists on the Plasma Membrane as an Intact Complex That Accepts Substrates and Effects Intramembrane Cleavage J. Biol. Chem., February 11, 2005; 280(6): 4383 - 4392. [Abstract] [Full Text] [PDF]

				D. Langui, N. Girardot, K. H. El Hachimi, B. Allinquant, V. Blanchard, L. Pradier, and C. Duyckaerts Subcellular Topography of Neuronal A{beta} Peptide in APPxPS1 Transgenic Mice Am. J. Pathol., November 1, 2004; 165(5): 1465 - 1477. [Abstract] [Full Text] [PDF]

				C. A. F. von Arnim, M. M. Tangredi, I. D. Peltan, B. M. Lee, M. C. Irizarry, A. Kinoshita, and B. T. Hyman Demonstration of BACE ({beta}-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy J. Cell Sci., October 15, 2004; 117(22): 5437 - 5445. [Abstract] [Full Text] [PDF]

				J. A. Cam, C. V. Zerbinatti, J. M. Knisely, S. Hecimovic, Y. Li, and G. Bu The Low Density Lipoprotein Receptor-related Protein 1B Retains {beta}-Amyloid Precursor Protein at the Cell Surface and Reduces Amyloid-{beta} Peptide Production J. Biol. Chem., July 9, 2004; 279(28): 29639 - 29646. [Abstract] [Full Text] [PDF]

				C. U. Pietrzik, I.-S. Yoon, S. Jaeger, T. Busse, S. Weggen, and E. H. Koo FE65 Constitutes the Functional Link between the Low-Density Lipoprotein Receptor-Related Protein and the Amyloid Precursor Protein J. Neurosci., April 28, 2004; 24(17): 4259 - 4265. [Abstract] [Full Text] [PDF]

				S. H. Pasternak, R. D. Bagshaw, M. Guiral, S. Zhang, C. A. Ackerley, B. J. Pak, J. W. Callahan, and D. J. Mahuran Presenilin-1, Nicastrin, Amyloid Precursor Protein, and {gamma}-Secretase Activity Are Co-localized in the Lysosomal Membrane J. Biol. Chem., July 11, 2003; 278(29): 26687 - 26694. [Abstract] [Full Text] [PDF]

				M. Gralle, M. M. Botelho, C. L. P. de Oliveira, I. Torriani, and S. T. Ferreira Solution Studies and Structural Model of the Extracellular Domain of the Human Amyloid Precursor Protein Biophys. J., December 1, 2002; 83(6): 3513 - 3524. [Abstract] [Full Text] [PDF]

				C. S. Ho, V. Marinescu, M. L. Steinhilb, J. R. Gaut, R. S. Turner, and E. L. Stuenkel Synergistic Effects of Munc18a and X11 Proteins on Amyloid Precursor Protein Metabolism J. Biol. Chem., July 19, 2002; 277(30): 27021 - 27028. [Abstract] [Full Text] [PDF]

				M. Marella, S. Lehmann, J. Grassi, and J. Chabry Filipin Prevents Pathological Prion Protein Accumulation by Reducing Endocytosis and Inducing Cellular PrP Release J. Biol. Chem., July 5, 2002; 277(28): 25457 - 25464. [Abstract] [Full Text] [PDF]

				M. M. Verbeek, I. Otte-Holler, J. A.M. Fransen, and R. M.W. de Waal Accumulation of the Amyloid-{beta} Precursor Protein in Multivesicular Body-like Organelles J. Histochem. Cytochem., May 1, 2002; 50(5): 681 - 690. [Abstract] [Full Text] [PDF]

				S.-R. Ji, Y. Wu, and S.-f. Sui Cholesterol Is an Important Factor Affecting the Membrane Insertion of beta -Amyloid Peptide (Abeta 1-40), Which May Potentially Inhibit the Fibril Formation J. Biol. Chem., February 15, 2002; 277(8): 6273 - 6279. [Abstract] [Full Text] [PDF]

				W. Xia, W. J. Ray, B. L. Ostaszewski, T. Rahmati, W. T. Kimberly, M. S. Wolfe, J. Zhang, A. M. Goate, and D. J. Selkoe Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta -protein generation PNAS, August 1, 2000; 97(16): 9299 - 9304. [Abstract] [Full Text] [PDF]

				P. G. Ulery, J. Beers, I. Mikhailenko, R. E. Tanzi, G. W. Rebeck, B. T. Hyman, and D. K. Strickland Modulation of beta -Amyloid Precursor Protein Processing by the Low Density Lipoprotein Receptor-related Protein (LRP). EVIDENCE THAT LRP CONTRIBUTES TO THE PATHOGENESIS OF ALZHEIMER'S DISEASE J. Biol. Chem., March 15, 2000; 275(10): 7410 - 7415. [Abstract] [Full Text] [PDF]

				B De Strooper and W Annaert Proteolytic processing and cell biological functions of the amyloid precursor protein J. Cell Sci., January 6, 2000; 113(11): 1857 - 1870. [Abstract] [PDF]

				S. Soriano, A. S. C. Chyung, X. Chen, G. B. Stokin, V. M.-Y. Lee, and E. H. Koo Expression of beta -Amyloid Precursor Protein-CD3gamma Chimeras to Demonstrate the Selective Generation of Amyloid beta 1-40 and Amyloid beta 1-42 Peptides within Secretory and Endocytic Compartments J. Biol. Chem., November 5, 1999; 274(45): 32295 - 32300. [Abstract] [Full Text] [PDF]

				L. Torroja, M. Packard, M. Gorczyca, K. White, and V. Budnik The Drosophila beta -Amyloid Precursor Protein Homolog Promotes Synapse Differentiation at the Neuromuscular Junction J. Neurosci., September 15, 1999; 19(18): 7793 - 7803. [Abstract] [Full Text] [PDF]

				R. G. Perez, S. Soriano, J. D. Hayes, B. Ostaszewski, W. Xia, D. J. Selkoe, X. Chen, G. B. Stokin, and E. H. Koo Mutagenesis Identifies New Signals for beta -Amyloid Precursor Protein Endocytosis, Turnover, and the Generation of Secreted Fragments, Including Abeta 42 J. Biol. Chem., July 2, 1999; 274(27): 18851 - 18856. [Abstract] [Full Text] [PDF]

				S. L. Sabo, L. M. Lanier, A. F. Ikin, O. Khorkova, S. Sahasrabudhe, P. Greengard, and J. D. Buxbaum Regulation of beta -Amyloid Secretion by FE65, an Amyloid Protein Precursor-binding Protein J. Biol. Chem., March 19, 1999; 274(12): 7952 - 7957. [Abstract] [Full Text] [PDF]

				L.-W. Jin, M. G. Hearn, C. E. Ogburn, N. Dang, D. Nochlin, W. C. Ladiges, and G. M. Martin Transgenic Mice Over-Expressing the C-99 Fragment of ßPP with an {alpha}-Secretase Site Mutation Develop a Myopathy Similar to Human Inclusion Body Myositis Am. J. Pathol., December 1, 1998; 153(6): 1679 - 1686. [Abstract] [Full Text] [PDF]

				D. S. Howland, S. P. Trusko, M. J. Savage, A. G. Reaume, D. M. Lang, J. D. Hirsch, N. Maeda, R. Siman, B. D. Greenberg, R. W. Scott, et al. Modulation of Secreted beta -Amyloid Precursor Protein and Amyloid beta -Peptide in Brain by Cholesterol J. Biol. Chem., June 26, 1998; 273(26): 16576 - 16582. [Abstract] [Full Text] [PDF]

				G. C. Peraus, C. L. Masters, and K. Beyreuther Late Compartments of Amyloid Precursor Protein Transport in SY5Y Cells Are Involved in beta -Amyloid Secretion J. Neurosci., October 15, 1997; 17(20): 7714 - 7724. [Abstract] [Full Text] [PDF]

				P. J. Tienari, N. Ida, E. Ikonen, M. Simons, A. Weidemann, G. Multhaup, C. L. Masters, C. G. Dotti, and K. Beyreuther Intracellular and secreted Alzheimer beta -amyloid species are generated by distinct mechanisms in cultured hippocampal neurons PNAS, April 15, 1997; 94(8): 4125 - 4130. [Abstract] [Full Text] [PDF]

				T. Yamazaki, E. H. Koo, and D. J. Selkoe Cell Surface Amyloid beta -Protein Precursor Colocalizes with beta 1 Integrins at Substrate Contact Sites in Neural Cells J. Neurosci., February 1, 1997; 17(3): 1004 - 1010. [Abstract] [Full Text] [PDF]

				N. R. Marquez-Sterling, A. C. Y. Lo, S. S. Sisodia, and E. H. Koo Trafficking of Cell-Surface beta -Amyloid Precursor Protein: Evidence that a Sorting Intermediate Participates in Synaptic Vesicle Recycling J. Neurosci., January 1, 1997; 17(1): 140 - 151. [Abstract] [Full Text] [PDF]

				A. F. Ikin, W. G. Annaert, K. Takei, P. De Camilli, R. Jahn, P. Greengard, and J. D. Buxbaum Alzheimer Amyloid Protein Precursor Is Localized in Nerve Terminal Preparations to Rab5-containing Vesicular Organelles Distinct from Those Implicated in the Synaptic Vesicle Pathway J. Biol. Chem., December 13, 1996; 271(50): 31783 - 31786. [Abstract] [Full Text] [PDF]

				G. Minopoli, P. de Candia, A. Bonetti, R. Faraonio, N. Zambrano, and T. Russo The beta -Amyloid Precursor Protein Functions as a Cytosolic Anchoring Site That Prevents Fe65 Nuclear Translocation J. Biol. Chem., February 23, 2001; 276(9): 6545 - 6550. [Abstract] [Full Text] [PDF]

				J. Walter, R. Fluhrer, B. Hartung, M. Willem, C. Kaether, A. Capell, S. Lammich, G. Multhaup, and C. Haass Phosphorylation Regulates Intracellular Trafficking of beta -Secretase J. Biol. Chem., April 27, 2001; 276(18): 14634 - 14641. [Abstract] [Full Text] [PDF]

				S. Soriano, D. C. Lu, S. Chandra, C. U. Pietrzik, and E. H. Koo The Amyloidogenic Pathway of Amyloid Precursor Protein (APP) Is Independent of Its Cleavage by Caspases J. Biol. Chem., July 27, 2001; 276(31): 29045 - 29050. [Abstract] [Full Text] [PDF]