Table Of ContentRESEARCH AND PERSPECTIVES IN ALZHEIMER'S DISEASE
Fondation Ipsen
Editor
Yves Christen, Fondation Ipsen, Paris (France)
Editorial Board
Yves Agid, Hopital 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)
]ean-Franfois Poncin, Hopital Pitie Salpetriere, Paris (France)
Franfoise Forette, Hopital Broca, Paris (France)
Fred Gage, Salk Institute, La Jolla (USA)
Carleton D. Gajdusek, National Institute of Health, Bethesda (USA)
Dmitry Goldgaber, State University of New York Stone Brook (USA)
John Hardy, Mayo Clinic, Jacksonville (USA)
Jean-Jacques Hauw, Hopital 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, Hopital Pitie Salpetriere, Paris (France)
Colin L. Masters, University of Melbourne, Parkville (Australia)
Stanley I. Rapoport, National Institute on Aging, Bethesda (USA)
Andre Rasco[, Hopital Purpan, Toulouse (France)
Barry Reisberg, New York University Medical Center, New York (USA)
Allen Roses, Duke University Medical Center, Durham (USA)
Dennis f. 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, Hopital 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-Verlag Berlin Heidelberg GmbH
K. Beyreuther Y. Christen C. L. Masters (Eds.)
Neurodegenerative Disorders:
Loss of Function Through Gain
of Function
With 28 Figures and 5 Tables
Springer
Beyreuther, Konrad, Dr. rer. nat. Dr. med. h.c.
ZMBH
University of Heidelberg
Im Neuenheimer Feld 282
69120 Heidelberg, Germany
E-mail: [email protected] ni-heidelberg.de
Christen, Yves, Ph. D.
Fondation IPSEN
Pour la Recherche Therapeutique
24, rue Erlanger
75781 Paris Cedex 16, France
E-mail: [email protected]
Masters, Colin L., M. D.
Department of Pathology and
The Mental Health Institute of Victoria
The University of Melbourne
Parkville, Victoria, 3052, Australia
E-mail: c.masters@pathology. unimelb.edu.au
ISSN 0945-6066
ISBN 978-3-642-07448-6
Library of Congress Cataloging-in-Publication Data
Neurodegenerative disorders : loss of function through gain of function I K. Beyreuther,
Y. Christen, C.L. Masters (eds.)
p. em. - (Research and perspectives in Alzheimer's disease)
Includes bibliographical references and index.
ISBN 978-3-642-07448-6 ISBN 978-3-662-04399-8 (eBook)
DOI 10.1007/978-3-662-04399-8
1. Nervous system - Degeneration. 2. Alzheimer's disease. 3. Amyloid
beta-protein - Pathophysiology. 4. Amyoloid beta-protein precursor - Pathophysiology. I.
Beyreuther, K. (Konrad), 1941 - II. Christen, Yves. III. Masters, Colin L. IV. Series.
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Preface
Fondation Ipsen sponsored a meeting in Paris in February 2000 on the emerging
paradigm-shift in our understanding of the major degenerative diseases which
affect the aging human brain. This book sumarizes our deliberations on some of
these major neurodegenerative diseases that are characterized by protein depos
its, and that are due to the pathogenic gain of function of an otherwise normal
neuronal protein.
For each of the major human neurodegenerative diseases covered in this
book - the most prominent being Alzheimer's disease - experimental models are
described, including cell culture systems and animal models which range from
the round worm, Caenorhabditis elegans, the fruitfly, Drosophila melanogaster, to
rodents. Remarkably, in the sporadic forms of these human diseases, only a
minor change in the level of production or turn-over of the relevant proteins is
sufficient to cause disease in late adult-hood. Neurodegeneration in Alzheimer's
disease, for example, usually results in symptoms and signs in the seventh to
eighth decades. In contrast, the development of protein deposits in transgenic
mice over-expressing the corresponding disease gene parallels the genetic forms
of the human diseases in regard to its manifestation occuring half-way through
its normal life-span, i.e. about 50 years in humans (the so-called "presenium")
and 9 to 12 months in the mouse. Nevertheless, these models have served to elu
cidate many of the pathways underlying the human disease processes, for
instance clarifying the neuronal origin of parenchymal and perivascular amyloid
in Alzheimer's disease and Creutzfeldt-Jakob disease. But there is much more to
be learned. The animal and the cellular models will also allow the investigation
of the intracellular and extracellular pathways involved in the causation of neuro
degeneration.
The main message from this book is that the different protein aggregation
processes may all be amenable to a small number of intervention steps based on
a common theme of the modulation of production, turnover and deposition of
the corresponding disease gene products. The next years will prove critical in
evaluating the possibilities of rational therapeutic strategies towards regaining
the loss of function through the amelioration of the abnormal gain of function.
January 2001 KONRAD BEYREUTHER
YVES CHRISTEN
COLIN MASTERS
Contents
The Natural History of Alzheimer's Disease: Minding the Gaps
in Understanding the Mechanisms of Neurodegeneration
C.L. Masters and K. Beyreuther . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Mechanisms of Motor Neuron Death in ALS
T.L. Williamson and D. W. Cleveland. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Pathological Mechanisms in Huntington's Disease
and Other Polyglutamine Expansion Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . 41
A. Lunkes, G. Yvert, Y. Trottier, D. Devys, and ].-L. Mandel
Prion Protein Biogenesis: Implications for Neurodegeneration
V.R. Lingappa and R.S. Hegde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
The Value of Transgenic Models for the Study of Neurodegenerative Diseases
D.L. Price, P.C. Wong, A.L. Markowska, G. Thinakaran, M.K. Lee,
L.]. Martin, ]. Rothstein, S.S. Sisodia, and D.R. Borchelt . . . . . . . . . . . . . . . . . . 67
Pathogenesis and Mechanism of Cerebral Amyloidosis
in APP Transgenic Mice
M. ]ucker, M. Calhoun, A. Phinney, M. Stalder, L. Bondolfi, D. Winkler,
M. Herzig, M. Pfeifer, S. Boncristiano, M. Tolnay, A. Probst, T. Deller,
D. Abramowski, K.-H. Wiederhold, C. Sturchler-Pierrat, B. Sommer,
and M. Staufenbiel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Alzheimer's Disease: Physiological and Pathogenetic Role
of the Amyloid Precursor Protein (APP), its AB-Amyloid Domain
and Free AB-Amyloid Peptide
K. Beyreuther and C.L. Masters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
The NEXT Step in Notch Processing and its Relevance
to Amyloid Precursor Protein
R. Kopan, S. Huppert, ].S. Mumm, M. T. Saxena, E.H. Schroeter, W.]. Ray,
and A. Coate ...................................................... 119
The Putative Role of Presenilins in the Transmembrane Domain Cleavage
of Amyloid Precursor Protein and Other Integral Membrane Proteins
B. De Strooper, A. Herreman, P. Cupers, K. Craessaerts, L. Serneels,
and W. Annaert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
VIII Contents
ApoE Receptors in the Brain: Novel Signaling Pathways
with Potential Relevance for Alzheimer's Disease
f. Herz, U. Beffert, T. Hiesberger, and M. Gotthardt ...................... 141
Homeoprotein Intercellular Transport:
Mechanisms, Significance and Applications
B. Allinquant, G. Mainguy, and A. Prochiantz .......................... 149
Overexpression of APPL, a Drosophila APP Homologue,
Compromises Microtubule Associated Axonal Transport
and Promote Synapse Formation
L. Torroja, M. Packard, V. Budnik, and K. White . . . . . . . . . . . . . . . . . . . . . . . . 159
A Gain of Function of the Huntington's Disease and Amyotrophic
Lateral Sclerosis - Associated Genetic Mutations May Be a Loss
of Bioenergetics
M.P. Real . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
List of Contributors
Abramowski, D.
Novartis Pharma, Ltd., 4002 Basel, Switzerland
Allinquant, B.
CNRS UMR 8542, Ecole Normale Superieure, 46, rue d'Ulm, 75005 Paris,
France
Annaert, W.
Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human
Genetics, Catholic University of Leuven and Flanders Interuniversitary
Institute for Biotechnology, 3000 Leuven, Belgium
Beal, M.P.
Department of Neurology and Neuroscience, Weill Medical College of Cornell
University and the New York Hospital - Cornell Medical Center, 525 East 681h
Street, New York, NY 10021, USA
e-mail: [email protected]
Beffert, U.
Department of Molecular Genetics, University of Texas Southwestern Medical
Center, 53223 Harry Hines Blvd., Dallas, TX 75390-9046, USA
Beyreuther, K.
Center for Molecular Biology (ZMBH), The University of Heidelberg,
69120 Heidelberg, Germany
e-mail: beyreuther@zmbh. uni-heidelberg. de
Boncristiano, S.
Neuropathology, Institute of Pathology, University of Basel, 4003 Basel,
Switzerland
Bondolfi, L.
Neuropathology, Institute of Pathology, University of Basel, 4003 Basel,
Switzerland
Borchelt, D.R.
Department of Pathology, The Johns Hopkins University School of Medicine,
558 Ross Research Building, 720 Rutland Avenue, Baltimore, MD 21205-2196,
USA
X List of Contributors
Budnik, V.
Department of Biology, University of Massachusetts, Amherst, Massachusetts
01003, USA
Calhoun, M.
Neuropathology, Institute of Pathology, University of Basel, 4003 Basel,
Switzerland
and Mount Sinai School of Medicine, New York, NY 10029, USA
Cleveland, D. W.
Ludwig Institute and Departments of Medicine and Neurosciences, University
of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0660, USA
e-mail: [email protected]
Craessaeerts, K.
Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human
Genetics, Catholic University of Leuven and Flanders Interuniversitary
Institute for Biotechnology, 3000 Leuven, Belgium
Cupers, P.
Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human
Genetics, Catholic University of Leuven and Flanders Interuniversitary
Institute for Biotechnology, 3000 Leuven, Belgium
De Strooper, B.
Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human
Genetics, Catholic University of Leuven and Flanders Interuniversitary
Institute for Biotechnology, 3000 Leuven, Belgium
Deller, T.
Institute of Anatomy, University of Freiburg, 79001 Freiburg, Germany
Devys, D.
Institut de Genetique et Biologie Moleculaire et Cellulaire, INSERM/CNRS/Uni
versite Louis Pasteur, BP 163, 67404 Illkirch Cedex, CU de Strasbourg, France
Goate, A.
Department of Psychiatry and Genetics, Washington University School
of Medicine, St. Louis, MO 63110, USA
Gotthardt, M.
Department of Molecular Genetics, University of Texas Southwestern Medical
Center, 53223 Harry Hines Blvd., Dallas, TX 75390-9046, USA
Hedge, R.S.
Laboratory of Cellular Oncology, National Institutes of Health, Bethesda, MD
20892, USA
