Immunization Against Alzheimer’s Disease and Other Neurodegenerative Disorders

130 Pages·2003·6.3 MB·English

by  A. Monsonego

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
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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.
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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
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Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO (2003) Neuropathology of
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Schenk D (2002) Amyloid-~ immunotheray for Alzheimer's disease: the end of the beginning.
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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]