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© The Rockefeller University Press, 0021-9525/2003/1/113 $5.00
The Journal of Cell Biology, Volume 160, Number 1, 113-123

Amyloidogenic processing of the Alzheimer ß-amyloid precursor protein depends on lipid rafts

¹ Max Planck Institute of Molecular Cell Biology and Genetics, D-01307 Dresden, Germany
² Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig Maximilians University, D-80336 Munich, Germany

Address correspondence to Kai Simons, Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, D-01307 Dresden, Germany. Tel.: 49-351-2102800. Fax: 49-351-2102900. E-mail: simons{at}mpi-cbg.de

Formation of senile plaques containing the ß-amyloid peptide (Aß) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by ß-secretase or by -secretase to initiate amyloidogenic (release of Aß) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Aß generation. Reducing cholesterol levels in N2a cells decreased Aß production. APP and the ß-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Aß in a cholesterol-dependent manner. Aß generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by ß-secretase, APP outside rafts undergoes cleavage by -secretase. Thus, access of - and ß-secretase to APP, and therefore Aß generation, may be determined by dynamic interactions of APP with lipid rafts.

Key Words: lipid rafts; ß-amyloid; BACE; Alzheimer's disease; endocytosis

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• Kawarabayashi, T., Shoji, M., Younkin, L. H., Wen-Lang, L., Dickson, D. W., Murakami, T., Matsubara, E., Abe, K., Ashe, K. H., Younkin, S. G. (2004). Dimeric Amyloid {beta} Protein Rapidly Accumulates in Lipid Rafts followed by Apolipoprotein E and Phosphorylated Tau Accumulation in the Tg2576 Mouse Model of Alzheimer's Disease. J. Neurosci. 24: 3801-3809 [Abstract] [Full Text]  
• von Tresckow, B., Kallen, K.-J., von Strandmann, E. P., Borchmann, P., Lange, H., Engert, A., Hansen, H. P. (2004). Depletion of Cellular Cholesterol and Lipid Rafts Increases Shedding of CD30. J. Immunol. 172: 4324-4331 [Abstract] [Full Text]  
• Sawamura, N., Ko, M., Yu, W., Zou, K., Hanada, K., Suzuki, T., Gong, J.-S., Yanagisawa, K., Michikawa, M. (2004). Modulation of Amyloid Precursor Protein Cleavage by Cellular Sphingolipids. J. Biol. Chem. 279: 11984-11991 [Abstract] [Full Text]  
• Cutler, R. G., Kelly, J., Storie, K., Pedersen, W. A., Tammara, A., Hatanpaa, K., Troncoso, J. C., Mattson, M. P. (2004). Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc. Natl. Acad. Sci. USA 101: 2070-2075 [Abstract] [Full Text]  
• Keller, R. K., Arnold, T. P., Fliesler, S. J. (2004). Formation of 7-dehydrocholesterol-containing membrane rafts in vitro and in vivo, with relevance to the Smith-Lemli-Opitz syndrome. J. Lipid Res. 45: 347-355 [Abstract] [Full Text]  
• Chyung, J. H., Selkoe, D. J. (2003). Inhibition of Receptor-mediated Endocytosis Demonstrates Generation of Amyloid {beta}-Protein at the Cell Surface. J. Biol. Chem. 278: 51035-51043 [Abstract] [Full Text]  
• Zacco, A., Togo, J., Spence, K., Ellis, A., Lloyd, D., Furlong, S., Piser, T. (2003). 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Protect Cortical Neurons from Excitotoxicity. J. Neurosci. 23: 11104-11111 [Abstract] [Full Text]  
• Shvartsman, D. E., Kotler, M., Tall, R. D., Roth, M. G., Henis, Y. I. (2003). Differently anchored influenza hemagglutinin mutants display distinct interaction dynamics with mutual rafts. JCB 163: 879-888 [Abstract] [Full Text]  
• Helmuth, L. (2003). Detangling Alzheimer's Disease. Sci Aging Knowl Environ 2003: oa2-2 [Abstract] [Full Text]  
• Scholefield, Z., Yates, E. A., Wayne, G., Amour, A., McDowell, W., Turnbull, J. E. (2003). Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's {beta}-secretase. JCB 163: 97-107 [Abstract] [Full Text]  
• Cheng, Q.-C., Tikhomirov, O., Zhou, W., Carpenter, G. (2003). Ectodomain Cleavage of ErbB-4: CHARACTERIZATION OF THE CLEAVAGE SITE AND m80 FRAGMENT. J. Biol. Chem. 278: 38421-38427 [Abstract] [Full Text]  
• Cordy, J. M., Hussain, I., Dingwall, C., Hooper, N. M., Turner, A. J. (2003). Exclusively targeting {beta}-secretase to lipid rafts by GPI-anchor addition up-regulates {beta}-site processing of the amyloid precursor protein. Proc. Natl. Acad. Sci. USA 100: 11735-11740 [Abstract] [Full Text]  
• Botelho, M. G., Gralle, M., Oliveira, C. L. P., Torriani, I., Ferreira, S. T. (2003). Folding and Stability of the Extracellular Domain of the Human Amyloid Precursor Protein. J. Biol. Chem. 278: 34259-34267 [Abstract] [Full Text]  
• Gong, Y., Chang, L., Viola, K. L., Lacor, P. N., Lambert, M. P, Finch, C. E., Krafft, G. A., Klein, W. L. (2003). Alzheimer's disease-affected brain: Presence of oligomeric A{beta} ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc. Natl. Acad. Sci. USA 100: 10417-10422 [Abstract] [Full Text]  
• Grbovic, O. M., Mathews, P. M., Jiang, Y., Schmidt, S. D., Dinakar, R., Summers-Terio, N. B., Ceresa, B. P., Nixon, R. A., Cataldo, A. M. (2003). Rab5-stimulated Up-regulation of the Endocytic Pathway Increases Intracellular {beta}-Cleaved Amyloid Precursor Protein Carboxyl-terminal Fragment Levels and A{beta} Production. J. Biol. Chem. 278: 31261-31268 [Abstract] [Full Text]  
• Sun, Y., Yao, J., Kim, T.-W., Tall, A. R. (2003). Expression of Liver X Receptor Target Genes Decreases Cellular Amyloid {beta} Peptide Secretion. J. Biol. Chem. 278: 27688-27694 [Abstract] [Full Text]  
• Berson, J. F., Theos, A. C., Harper, D. C., Tenza, D., Raposo, G., Marks, M. S. (2003). Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis. JCB 161: 521-533 [Abstract] [Full Text]  

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