Immunization Against Alzheimer’s Disease and Other Neurodegenerative Disorders PDF
Preview Immunization Against Alzheimer’s Disease and Other Neurodegenerative Disorders
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) 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, Inserm 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) Carlton D. Gajdusek, National Institute of Health, Bethesda (USA) Dmitry Goldgaber, State University of New York Stony 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 of 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) Edouard Zarifian, Centre Hospitalier Universitaire, Caen (France) Springer Berlin Heidelberg New York Hong Kong London Milan Paris Tokyo J. D. Selkoe Y. Christen (Eds.) Immunization Against Alzheimer's Disease and Other N eurodegenerative Disorders With 39 Figures and 5 Tables Springer Selkoe. Dennis ]., MD Center for Neurologic Diseases Harvard Medical School and Brigham and Women's Hospital 77 Avenue Louis Pasteur, HIM 730 Boston, MA 02115 USA e-mail: [email protected] Christen, Yves, Ph.D. Fondation IPSEN Pour la Recherche Therapeutique 24, rue Erlanger 75781 Paris Cedex 16 France e-mail: [email protected] ISSN 0945-6066 ISBN-13:978-3-M2-63937 -I e-ISBN-13:978-3-642-59332-1 DOl: 10.1007/978-3-642-59332-1 Cataloging-in-Publication Data applied for Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at <http://dnb.ddb.de>. 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, broadcasting, reproduction on microfilms or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 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 a member of BertelsmannSpringer Science + Business Media GmbH http://www.springer.de © Springer-Verlag Berlin Heidelberg 2003 Softc<M!r reprint of the hardcover 1st edition 2003 The use of general descriptive names, registered names, trademarks, etc. in this publications does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective 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, 69126 Heidelberg, Germany Cover design: design & production, 69121 Heidelberg, Germany Typesetting and Repro: AM-productions GmbH, 69168 Wiesloch, Germany Printed on acid-free paper 27110914250Re -5 4 3 2 1 0 Preface The July 1999 publication in Nature (Schenk et al. 1999) about the promising ef fects in mice of immunization by p-amyloid (AP) stimulated substantial research efforts and high hopes. In retrospect, this study appears simultaneously logical, consistent as it is with the amyloid theory central today in the field of Alzheimer's disease (AD) studies, and paradoxical, because it involved using the toxic sub stance itself for a treatment benefit. It has been confirmed and extended by seve ral others (Janus et al. 2000, Morgan et al. 2000, Schenk 2002). Together they sug gest that such a "vaccination" can clean the brain of amyloid deposits and favor ably modify the animal's behavior. The research thus begun opens up multiple perspectives for experimentation and for treatment. Clinical trials with A~42 (un der the name AN 1792) began: the phase I studies were encouraging, but the phase II trial, with 375 patients, had to be stopped in January 2002 because of se rious side effects (17 cases of meningoencephalitis), that is, only two months be fore the XVIUO Medical Research Colloquium devoted by the Fondation Ipsen to AD. This book constitutes the proceedings of that meeting, which took place in Paris on 13 March 2002. The meeting's aim was not limited to the therapeutic prospects for these stu dies. Most of the specialists present thought that the failure of this first treatment attempt represented not the end of this research pathway but, more probably, in the words of one of the participants, "the end of the beginning" (Schenk 2002). Other possibilities are emerging, such as other immunization routes (nasal, in particular; Weiner et al. 2000), the use of different peptides, or passive immuniza tion directly with the antibody rather than the peptide (Bard et al. 2000; Backsai et al. 2001). Moreover, many questions arise - about the possibility of immunization against a protein native to the organism, the specific type of immune reactions associated with immunization against AP, and immune reactions in elderly sub jects. Other studies lead us to wonder about whether the vaccine has necessarily to access to the brain, insofar as there seems to be a dynamic equilibrium bet ween the AP of the central nervous system and plasma AP: anti-Ap antibodies may be able to act as a "peripheral sink" and alter this equilibrium (DeMattos et al. 2001). On the other hand, thanks to the work on immunization against AD, unpredic ted discoveries have been made. For example, works using multiphoton micro scopy have shown that, in addition to its preventive effect, immunotherapy can clear the existing senile plaques in the brain (Backsai et al. 2001). VI Preface The recent analysis of human neuropathology after immunization with AN-1792 Auggest that the immune response generated against A~ elicited clea rance of A~ plaques in the first patient studied (Nicoll et al. 2003). It will be especially interesting to see whether the attenuation of the amyloid pathology is accompanied by clinical improvement, and if so, how much. What we can expect from this work is that it will provide clinical confirmation of the vali dity of the amyloid theory, today supported by substantial theoretical and experi mental arguments but not yet demonstrated in humans (Hardy and Selkoe 2002). Finally, if its medical value is confirmed, immunization may be a therapeutic approach for many neurodegenerative diseases. These seem to involve the aggre gation of a particular peptide in the brain - AP for AD, a-synuctein for Parkin son's disease and Lewy body dementia, tau in diverse frontal lobe dementias (but also in AD), the Prp Sc protein in prion diseases, etc. Immunization trials may the refore be useful in several diseases. This research therefore opens up numerous prospects and raises as many questions. These justify its choice as the theme in the series of Medical Research Colloquia sponsored by the Fondation Ipsen. It goes without saying that the orga nizers' and editors' objective for this book is not to arouse false hopes for a thera peutic project that must still be proven but to discuss the available information and the questions it raises. April 2003 Yves Christen Acknowledgments We would like to thank the various people who helped in organizing this collo quium, in particular Jacqueline Mervaillie, as well as MaryLynn Gage for her edi torial assistance. References Backsai B, Kajdasz S, Christie R, Carter C, Games D, Seubert P, Schenk D, Hyman B (2001) Ima ging of amyloid ~ deposits in brains ofliving mice permits direct observation of clearance of plaques with immunotherapy. Nature Med 7:369-372. Bard F, Cannon C, Barbour R, Burke R-L, Games D, Grajeda H, Guido T, Hu K, Huang I, Iohnson Wood K, Khan K, Kholodenko D, Lee M, Lieberburg 1, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T (2000) Peripherallyadministe red autoantibodies against amyloid ~-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med 6:916-919. DeMattos RB, Bales KR, Cummins DI, Dodart I-C, Paul SM, Holtzman DM (2001) Peripheral anti-A~ antibody alters CNS and plasma A~ clearance and decreases brain A~ burden in a mouse model of Alzheimer's disease. Proc Nat! Acad Sci USA 98:8850-8855. Hardy J, Selkoe D (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353-356. Ianus C, Pearson I, McLaurin I, Mathews PM, liang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French I, Mount HTI, Nixon RA, Mercken M, Bergeron C, Fraser PE, St. George-Hyslop P, Preface VII Westaway (2000) A~ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408:979-982. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, Dicarlo G, Wilcock D,Connor K, Hatcher J, Hope C, Gordon M,Arendash GW (2000) A~ peptide vac cination prevents memory loss in an animal model of Alzheimer's disease. Nature 408:982- 985. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Na ture Med 9:448-452. Schenk D (2002) Amyloid-~ immunotheray for Alzheimer's disease: the end of the beginning. Nature Rev Neurosci 3:824-828. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg 1, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Im munization with amyloid-~ attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173-177 Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Issazadeh S, Hancock WW, Selkoe DJ (2000) Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann NeuroI48:567-579. Contents Immunologic and Tolerogenic Aspects of Amyloid Beta-Peptide: Implications for the Pathogenesis and Treatment of Alzheimer's Disease A. Monsonego and H.L. Weiner . . . . . . . . . . . . . . . . . . . . . . . . 1 Towards Diagnosis and Treatment of Alzheimer's Disease B. Solomon ........................... . . . . .. 11 Characterization of Amyloid Beta Vaccination Strategies in Mice C. Cao, K.E. Ugen, C. Dickey, D. Wilcock, Y. Bai, M.N. Gordon, and D. Morgan ... . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 21 Cognitive Characteristics of TgAPP CRND8 Mice Immunised with Beta Amyloid Peptide C. Janus, H.-S. Johnson, J. McLaurin, P. Fraser, P. St.George-Hyslop, and D. Westaway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Intranasal A~-Vaccination as an Approach to Treating ~-Amyloidosis D.J. Selkoe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ... 45 Improvements in Intranasal Amyloid-~ (A~) Immunization in Mice c.A. Lemere, E. T. Spooner, J.P. Leverone, J.D. Clements . . . . . . .. .... 59 Antibody Therapy Against ~-Amyloid to Treat Alzheimer's Disease P. Bard, P. Seubert, D. Schenk, and T. Yednock . . . . . . . . . . . . . . . . .. 75 Effects of a Peripheral Anti-A~ Antibody on Plasma and CNS A~ Clearance D.M. Holtzman, K.R. Bales, S.M. Paul, and R.B. DeMattos ... 85 Multiphoton Microscopy: Imaging Plaques and Reversal of Plaques - a Transgenic Model by Multiphoton Microscopy B. T. Hyman and B.J. Bacskai ........................... 97 Antibodies as Therapeutic Agents for Prion Disease D. Peretz, R.A. Williamson, K. Kaneko. D. R. Burton, and S.B. Prusiner . 107 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 125 List of Contributors Bacskai, B.J. Massachusetts General Hospital/Harvard Medical School, Department of Neurology, 114, 16th Street (CAGN 2009), Charlestowr MA 02129, USA, e-mail [email protected] Bai, Y. Dept. of Medical Microbiology and Immunology, University of South Florida College of Medicine, MDC 10,12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA Bales, K.R. Neuroscience Discovery Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA Bard, F. Elan Pharmaceuticals 800 Gateway Blvd, South San Francisco, CA 94080, USA, e-mail: [email protected] Burton, D.R. Department of Immunology and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA Cao, C. Dept. of Medical Microbiology and Immunology, University of South Florida College of Medicine, MDC 10,12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA Clements, J.D. Department of Microbiology and Immunology, Program in Molecular and Pathogenesis and Immunity, Tulane University School of Medicine, New Orleans, LA 70112, USA DeMattos, R.B. Center for the Study of Nervous System Injury, Alzheimer's Disease Research Center, Dept. of Neurology, XII List of Contributors Washington University School of Medicine, 660 S. Euclid Ave., Box 811, St. Louis, MO 63110, USA Dickey, C. Alzheimer Research Laboratory, Department of Pharmacology, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA Fraser, P. Centre for Research in Neurodegenerative Disease, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M9B 5K3, Canada Gordon, M.N. Alzheimer Research Laboratory, Department of Pharmacology, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA Holtzman, D.M. Center for the Study of Nervous System Injury, Alzheimer's Disease Research Center, Dept. of Neurology, Molecular Biology and Pharmacology, Washington University School of Medicine, 660 S. Euclid Ave., Box 811, St. Louis, MO 63110, USA, e-mail: [email protected] Hyman, B.T. Massachusetts General Hospital/Harvard Medical School, Department of Neurology, 115, 16th Street (CAGN 2009), Charlestown, MA 02129, USA, e-mail: [email protected] Janus, C. Centre for Research in Neurodegenerative Disease, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M9B 5K3, Canada Johnson, H.-S. Centre for Research in Neurodegenerative Disease, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M9B 5K3, Canada Kaneko,K. National Institute of Neuroscience, Tokyo 187-8502, Japan Lemere, C.A. Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, e-mail: [email protected]
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