RESEARCH AND PERSPECTIVES IN ALZHEIMER'S DISEASE Fondation Ipsen Editor Yves Christen, Fondation Ipsen, Paris (France) Editorial Board Yves Agid, H6pital Pitie Salpetriere, Paris (France) Albert Aguayo, McGill University, Montreal (Canada) Luigi Amaducci, University of Florence, Florence (Italy) Brian H. Anderton, Institute of Psychiatry, London (GB) Raymond T. Bartus, Alkermes, Cambridge (USA) Anders Bjorklund, University of Lund (Sweden) Floyd Bloom, Scripps Clinic and Research Foundation, La Jolla (USA) Franfois Boller, Inserm U 324, Paris (France) Carl Cotman, University of California, Irvine (USA) Peter Davies, Albert Einstein College of Medicine, New York (USA) Andre Delacourte, Insterm U 422, Lille (France) Steven Ferris, New York University Medical Center, New York (USA) Jean-Franfois Foncin, H6pital Pitie Salpetriere, Paris (France) Franfoise Forette, H6pital Broca, Paris (France) Fred Gage, Salk Institute, La Jolla (USA) Dmitry Goldgaber, State University of New York Stone Brook (USA) John Hardy, Mayo Clinic, Jacksonville (USA) Jean-Jacques Hauw, H6pital Pitie Salpetriere, Paris (France) Claude Kordon, Inserm U 159, Paris (France) Kenneth S. Kosik, Harvard Medical School, Center for Neurological Diseases and Brigham and Women's Hospital, Boston (USA) Jacques Mallet, H6pital Pitie Salpetriere, Paris (France) Colin L. Masters, University of Melbourne, Parkville (Australia) Stanley I. Rapoport, National Institute on Aging, Bethesda (USA) Andre Rascol, H6pital Purpan, Toulouse (France) Barry Reisberg, New York University Medical Center, New York (USA) Allen Roses, Duke University Medical Center, Durham (USA) Dennis J. Selkoe, Harvard Medical School, Center for Neurological Diseases and Brigham and Women's Hospital, Boston (USA) Michael L. Shelanski, Columbia University, New York (USA) Pierre-Marie Sinet, H6pital Necker, Paris (France) Peter St. George-Hyslop, University of Toronto, Toronto (Canada) Robert Terry, University of California, La Jolla (USA) Henry Wisniewski, Institute for Basic Research in Development Disabilities, Staten Island (USA) Edouard Zarifian, Centre Hospitalier Universitaire, Caen (France) Springer Berlin Heidelberg New York Barcelona Budapest Hong Kong London Milan Paris Santa Clara Singapore Tokyo S.G. Younkin R.E. Tanzi Y. Christen (Eds.) Presenilins and Alzheimer's Disease With 17 Figures and 4 Tables Springer Younkin, S.G., M.D., Ph.D. Mayo Clinic Jacksonville 4500 San Pablo Road Jacksonville, FL 32224 USA Tanzi, R.E., Ph.D. Genetics and Aging Unit and the Department of Neurology Massachusetts General Hospital-East Harvard Medical School 149, 13th Street Boston, MA 02129-9142 USA Christen, Y., Ph.D. Fondation IPSEN 24, rue Erlanger 75651 Paris Cedex 16 France ISSN 0945-6066 ISBN-13:978-3-642-72105-2 e-ISBN-13:978-3-642-72103-8 DOl: 10.1007/978-3-642-72103-8 Library of Congress Cataloging-in-Publication Data Presenilins and Alzheimer's disease 1 S. G. Younkin, R. E. Tanzi, Y. Christen (eds.). p. cm. - (Research and perspectives in Alzheimer's disease)Inciudes bibliographical references and index.ISBN-13:978-3- 642-721Os-2(hardcover)1.Alzheimer's disease - Molecular aspects. 2. Alzheimer's disease - Genetic aspects. 3. Presenilins. I. Younkin, S. G. (Steven G.) II. Tanzi, Rudolph E. III. Christen, Yves. IV. Series. RC523.P74 1998 616.8'3107-dC21 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcast ing' reproduction on microfilm or in any other way, and storage in data banks. Duplication of this pub lication or parts thereof is permitted ouly under the provisions of the German Copyright Law of Sep tember 9, 1965, in its current version, and permission for use must always be obtained from Springer Verlag. Violations are liable for prosecution under the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1998 Softcover reprint of the hardcover 1st edition 1998 The use of general descriptive names, registered names, trademarks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant pro tective laws and regulations and therefore free for general use. Product Liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Production: PRO EDIT GmbH, D-69126 Heidelberg Cover design: Design & Production, D-69121 Heidelberg Typesetting: Mitterweger Werksatz GmbH, Plankstadt SPIN: 10551710 27/3136 - 5 4 3 2 1 0 - Printed on acid-free paper Preface Molecular and biochemical studies of Alzheimer's disease have recently under gone a major revolution with the discovery of the presenilin genes. Since 1995 when these genes were first identified to carry defects responsible for up to half of early onset familial Alzheimer's disease cases (Sherrington et al. 1995; Levy-Lahad et al. 1995), over 50 Alzheimer-associated mutations have been found in the prese nilin genes, PSI and PS2 (reviewed in Tanzi et al. 1996). Over 200 papers have been published regarding the characterization of the presenilins. Not since the amyloid ~ protein Precursor (APP) was isolated in 1987 (Kang et al. 1987; Goldga ber et al. 1987; Robakis et al. 1987; Tanzi et al. 1987) has the discovery of novel genes had such an impact on the field of Alzheimer's disease research. To whit, five separate sessions at the 1997 Society for Neuroscience Meeting are devoted solely to studies of the presenilins. The presenilins genes have clearly taken the field of Alzheimer's disease research by storm and appropriately so since defects in these genes can cause Alzheimer's disease as early as in one's late twenties. One of the greatest revelations to arise from molecular studies of the preseni lins is the finding that, like the familial Alzheimer's disease mutations in APP, the mutations in the presenilin genes lead to increased production and secretion of the longer form of the A~ peptide, A~42 (Scheuner et al. 1995), which seeds ~­ amyloid formation in the brain. The presenilins have also been implicated in the process of programmed cell death (apoptosis; Kim et al. 1997; Wolozin et al. 1997). At the more basic biological level, these proteins have been linked to the developmental pathway involving the Notch genes (Levitan and Greenwald, 1995). These and other findings have provided great clues to the roles of the pre senilin in both health and disease. It is thus appropriate that the Fondation IPSEN organized a meeting in July of 1997 to bring together a group of leaders in the area of presenilin biology to discuss ideas regarding the biological function of the presenilins and how defects in these genes cause the earliest onset form of Alzheimer's disease. An understanding of the mechanisms by which mutations in the presenilin genes cause neurodegeneration and dementia should greatly facili tate the development of novel strategies for treating Alzheimer's disease and related disorders. January 1998 Rudolph TANZI Steven YOUNKIN Yves CHRISTEN VI Preface References Goldgaber D, Lerman JI, McBride OW, Saffiotti U, Gajdusek DC (1987) Characterization of chromo so mal localization of a cDNA encoding brain amyloid of fibril protein. Science 235:877-880 Kang J, Lemaire H, Unterbeck A, Salbaum JM, Masters CL, Grzeschik K, Multhaup G, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell surface receptor. Nature 325:733-736 Kim TW, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE (1997) Alternative cleavage of Alzheimer associated presenilins during apoptosis by a caspase-3 family protease. Science 277:373-376 Levitan D, Greenwald I (1995) Facilitation of lin-12-mediated signalling by sel-12, a caenorhabditis elegans S182 Alzheimer's disease gene. Nature 377:351-354 Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima JM, Pettingell WH, Yu C, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu Y-H, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellen berg GD, Tanzi RE (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269:973-977 Robakis NK, Ramakrishna N, Wolfe G, Wisniewski HM (1987) Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci USA 84:4190-4194 Scheuner D, Eckmann C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi RE, Wasco W, Lannfelt L, Selkoe D, Younkin S (1996) Secreted amyloid ~-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations lin ked to familial Alzheimer's disease. Nature Med 2:864-870 Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin J-F, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov Y, Pollen D, Wasco W, Haines JL, Da Silva R, Pericak-Vance M, Tanzi RE, Roses AD, Fraser PE, Rom mens JM, St George-Hyslop PH (1995) Cloning of a novel gene bearing missense mutations in early onset familial Alzheimer's disease. Nature 375:754-760 Tanzi RE, Gusella JF, Watkins PC, Bruns GAP, St George-Hyslop P, van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987) Amyloid ~ protein gene: cDNA, mRNA distribution and genetic linkage near the Alzheimer locus. Science 235: 880 -884 Tanzi RE, Kovacs DM, Kim T-W, Moir RD, Guenette SY, Wasco W (1996) The gene defects responsible for familial Alzheimer's disease. Neurobiol Dis 3:159-168 Wolozin B, Iwasaki K, Vito P, Ganjei K, Lacana E, Sunderland T, Zhao B, Kusiak JW, Wasco W, D' Ada mio L (1996) PS2 participates in cellular apoptosis: constitutive activity conferred by Alzheimer mutation. Science 274:1710-1713 Acknowledgments: The editors wish to thank Mary Lynn Gage for editorial assistance and Jacqueline Mervaillie for the organization of the meeting in Paris. Contents Molecular Genetics of the Presenilins in Alzheimer's Disease P.E. Fraser, G. Yu, G. Levesque, M. Ikeda, M. Nishimura, E. Rogaeva, D. Westaway, P.H. St.George-Hyslop and G.A. Carlson ................... . Alzheimer's Disease: A Matter of Dominance J. Hardy and M. Hutton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Alternative Endoproteolysis of the Presenilins and Familial Alzheimer's Disease R.E. Tanzi, T. W. Kim, D.M. Kovacs, W. Wasco, R.D. Moir, W. Pettingell, J. Henderson, and R. Mancini . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 19 The APP and PS1/2 Mutations Linked to Early Onset Familial Alzheimer's Disease Increase the Extracellular Concentration of A~1-42(43) .......... , 27 S.G. Younkin Metabolism and Function of Presenilin 1 5.5. Sisodia, G. Thinakaran, P.e. Wong, D.R. Borchelt, M.K. Lee, A. Doan, J. Regard, H. Chen, H. Zheng, e. Eckman, H.H. Slunt, T. Ratovitsky, e. F. Davenport, Harris, L.H. T. Van der Ploeg, S.G. Younkin, N.A. Jenkins, N.G. Copeland, and D.L. Price ....................................... 35 Mechanistic Studies of the Effect of Presenilins 1 and 2 on APP Metabolism D,f. Selkoe, W. Xia, J. Zhang, M.B. Podlisny, e.A. Lemere, M. Citron, and E.H. Koo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Presenilin 2 - APP Interactions W. Wasco, R.E. Tanzi, R.D. Moir, A.e. Crowley, D.E. Merriam, D.M. Romano, P.D. Jondro, and B.A. Kellerman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 The Cellular Biology of Presenilin Proteins and a Novel Mechanism of Amyloid ~-Peptide Generation e. Haass, J. Walter, A. Capell, e. Wild-Bode,]. Griinberg, T. Yamazaki, e. 1. Ihara, 1. Zweckbronner, Jakubek, and R. Baumeister. . . . . . . . . . . . . . . .. 71 VIII Contents Regulation of Presenilin 1 Phosphorylation and Transcriptional Activation of Signal Transduction-Induced Genes by Muscarinic Receptors U. Langer, C. Albrecht, M. Mayhaus, J. Velden, H. Wiegmann, J. Klaudiny, D. Muller, H. von der Kammer, and R.M. Nitsch... ... . ...... .. ..... ... 79 Neuronal Regulation of Presenilin-l Processing H. Hartmann, J. Busciglio and B.A Yankner . . . . . . . . . . . . . . . . . . . . . . . . . . .. 85 Transgenic Approaches to the Study of Alzheimer's Disease K. Duff· ....... ·· ............. ·................................... 93 Subject Index .................................................... 97 List of Contributors Albrecht, C. Center for Molecular Neurobiology, University of Hamburg, Martinistr. 52, 20246 Hamburg, Germany Baumeister, R. Laboratory of Molecular Biology/Genzentrum of the University of Munich, 81377 Munich, Germany Borchelt, D.R. Department of Pathology and the Neuropathology Laboratory, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA Busciglio, J. Department of Neurology, Harvard Medical School and The Children's Hospital, Enders 260, 300 Longwood Avenue, Boston, MA 02115, USA Capell, A. Central Institute for Mental Health, Department of Molecular Biology, J5, 68159 Mannheim, Germany Carlson, G.A. McLaughlin Research Institute 1520, 23rd Street South, Great Falls, Montana 59409, USA Chen, H. The Neuropathology Laboratory, The John Hopkins University School of Medi cine, Baltimore, MD 21205, USA Citron, M. Amgen, Inc., Thousand Oaks, CA 91320-1789, USA Copeland, N.G. Mammalian Genetics Laboratory, ABL-Basis Research Program, NCI-Frederick Cancer Center Research & Development, Frederick, MD 21701, USA X Contributors Crowley, A.C. Genetics and Aging Unit and the Department of Neurology, Massachusetts Gen eral Hospital, Harvard Medical School, 149, 13th Street, Charlestown and Boston MA 02129-9142, USA Davenport, F. The Neuropathology Laboratory, The John Hopkins University School of Medi cine, Baltimore, MD 21205, USA Doan, A. The Neuropathology Laboratory, The John Hopkins University School of Medi cine, Baltimore, MD 21205, USA DUff, K. Mayo Clinic Jacksonville, 4500 San Pablo Rd., Jacksonville, FL 32224, USA Eckman, C. Mayo Clinic Jacksonville, 4500 San Pablo Rd., Jacksonville, FL 32224, USA Fraser, RE. Centre for Research in Neurodegenerative Disease, Department of Medicine (Neurology), The Toronto Hospital, Tanz Neuroscience Bldg., 6, Queen's Park Crescent, Toronto, Ontario, Canada M5S 1A8 Grunberg, J. Central Institute for Mental Health, Department of Molecular Biology, J5, 68159 Mannheim, Germany Haass, C. Central Institute for Mental Health, Department of Molecular Biology, J5, 68159 Mannheim, Germany Hardy, J. Mayo Clinic Jacksonville, 4500 San Pablo Rd., Jacksonville, FL 32224, USA Harris, C. The Neuropathology Laboratory, The John Hopkins University School of Medi cine, Baltimore, MD 21205, USA Hartmann, H. Department of Neurology, Harvard Medical School and The Children's Hospital, Enders 260, 300 Longwood Avenue, Boston, MA 02115, USA Henderson, J. Genetics and Aging Unit and the Department of Neurology, Massachusetts Gen eral Hospital, Harvard Medical School, 149, 13th Street, Charlestown, MA 012129, USA