Chikako Tanaka

Patrick l. McGeer

Yasuo Ihara

(Editors)

Neuroscientific Basis of Dementia

Springer Basel AG

Editors

Prof. Dr. Chikako Tanaka Hyogo Institute for Aging Brain and Cognitive Disorders 520, Saisho-ko Himeji 670-0981 Japan

Prof. Dr. Yasuo Ihara Department of Neuropathology Faculty of Medicine University of Tokyo 7-3-1 Hongo, Bunkyo-ku Tokyo 113-0033 Japan

Prof. Dr. Patrick l. McGeer Kinsmen Laboratory of Neurological Research University of British Columbia 2255 Wesbrook Mall Vancouver, B.C., V6T 1Z3 Canada

A CIP catalogue record for this book is available from the Library of Congress, Washington, D.C., USA

Deutsche Bibliothek Cataloging-in-Publication Data Neuroscientific basis of dementia led. by Chikako Tanaka ... - Basel ; Boston; Berlin: Birkhauser, 2001

ISBN 978-3-0348-9482-1 ISBN 978-3-0348-8225-5 (eBook) DOI 10.1007/978-3-0348-8225-5

The publisher and editor can give no guarantee for the information on drug dosage and administration contained in this publication. The respective user must check its accuracy by con­sulting other sources of reference in each individual case.

The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws and regulations or free for general use.

This work is subject to copyright. AII rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. For any kind of use permission of the copyright owner must be obtained.

© 2001 Springer Basel AG Origina1ly published by Birkhauser Verlag in 2001

Printed on acid-free paper produced from chlorine-free pulp. TFC 00

Cover design: Micha Lotrovsky Cover illustration: Colocalization of a protein kinase (PKN, red) and a microtubule-associated protein (tau, green) in the CA 1 pyramidal neurons of hippocampus in patients with Alzheimer disease. Tau was probed with a phospho-tau-specific monoclonal antibody (AT8). The picture is reproduced by kind permission of Toshio Kawamata (p. 121ff).

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Table of contents

List of contributors IX

Preface .......................................................... XXI

Special lectures

A tale of protein kinase C and membrane lipid signaling Yasutomi Nishizuka .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Complement, neuroinflammation and neuronal degeneration in Alzheimer disease Patrick L. McGeer, Edith G. McGeer and Koji Yasojima ..................... 15

Memory and its impairment

Neurobiological mechanisms by which emotional arousal influences long-term memory formation Larry Cahill ...................................................... 23

Amygdalar damage and memory impairment in Alzheimer's disease Etsuro Mori ...................................................... 35

Neural substrate for spatial memory in the monkey hippocampus Ryoi Tamura and Taketoshi Ono ....................................... 43

Involvement of CaM kinase II and mitogen-activated protein kinase in hippocampal long-term potentiation Eishichi Miyamoto, Jie Liu, Kohji Fukunaga and Dominique Muller ........... 49

Pathogenesis of dementia - tau

Transgenic mice overexpressing the shortest human tau isoform develop a progressive tauopathy Takeshi Ishihara, Ming Hong, Bin Zhang, John Q. Trojanowski and Virginia M.-y' Lee .............. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

VI Table of contents

Tau and neurodegenerative disease: genetics and pathogenetic mechanisms Gerard D. Schellenberg, Ian D'Souza, Parvoneh Poorkaj and Thomas D. Bird

Tau mutations altering splicing of tau exon 10 in japanese frontotemporal dementia Minoru Yasuda, Junichi Takamatsu, Osamu Komure, Sadako Kuno, Ian D'Souza, Toshio Kawamata, Masato Hasegawa, Takeshi Iwatubo, Parvoneh Poorkaj,

71

Michel Goedert, Gerard D. Schellenberg and Chikako Tanaka ................ 81

Amyotrophic lateral sclerosis/parkinsonism-dementia complex of the Kii peninsula of Japan (Kii ALSIPDC) may be a familial tauopathy. Epidemiological trends, clinical features, neuropathology and molecular genetics Shigeki Kuzuhara, Ryogen Sasaki, Yasumasa Kokubo and Yugo Narita .......... 85

Senile dementia of the neurofibrillary tangle type (SD-NFf): a clinical, neuropathological and molecular genetic study Masahito Yamada, Yoshinori Itoh, Nobuyuki Sodeyama, Naomi Suematsu, Eiichi Otomo, Masaaki Matsushita and Hirdehiro Mizusawa ................. 95

The dual role of tau in cell polarisation and organelle trafficking Eva-Maria Mandelkow, Jacek Biernat, Karsten Stamer, Bernhard Trinczek and Eckhard Mandelkow ............................................ 101

Rearrangement of microtubule networks by tau bearing missense mutations Naruhiko Sahara, Takami Tomiyama and Hiroshi Mori .............. . . . . . . . . 113

Possible role of tau phosphorylation on ER membrane in Alzheimer pathology Toshio Kawamata, Taizo Taniguchi, Hideyuki Mukai, Takeshi Hashimoto, Hiroshi Hasegawa, Niu San-Yu, Akira Terashima, Masamichi Nakai, Minoru Yasuda, Kiyoshi Maeda, Yoshitaka Ono, Koho Miyoshi and Chikako Tanaka 121

Pathogenesis of dementia - synuclein

Pathogenesis of dementia: updating the role of synuclein pathology in sporadic and hereditary Alzheimer's disease John E. Duda, Virginia M.-Y. Lee and John Q. Trojanowski .................. 131

a-SynucleinlNACP and neurodegeneration Seigo Tanaka, Masanori Takehashi, Naomi Matoh and Kunihiro Ueda 137

a-Synuclein fibrillogenesis as target for drug development Martin Citron, Linda Narhi, Jette Wypych, Jean-Claude Louis and Anja Leona Biere .................................................. 143

Table of contents VII

Pathogenesis of dementia - presenilin and amyloid

Genetics of early-onset Alzheimer disease Peter H. St George-Hyslop ........................................... 153

Lessons from presenilin domain analysis: endoproteolytic processing and enhanced A~42 production mediated by FAD-linked variants Gopal Thinakaran, Carlos A. Saura, Taisuke Tomita, Toshiyuki Honda and Takeshi Iwatsubo ............................................... 167

Amyloid and presenilins in the pathobiology of Alzheimer's disease Takeshi Iwatsubo and Taisuke Tomita ................................... 177

Role of presenilin in APP processing and A~ production Weiming Xia and Dennis l. Selkoe ..................................... 183

Impairment of response to ER stress in presenilin 1 mutant Takashi Kudo, Kazunori Imaizumi, Taiichi Katayama, Naoya Sato, Yuka Nakano, Yuka linno, Yuko Segawa, lunji Takeda, Masaya Tohyama and Masatoshi Takeda .............................................. 193

Mechanism of neuron death in Alzheimer's disease Akihiko Takashima, Ohoshi Murayama, Toshiyuki Honda, Xiaoyan Sun and Shinji Sato .................................................... 201

Notch3 gene in CADASIL syndrome: mutation frequencies in Japanese and its expression and processing Keikichi Takahashi, Satoshi Kotorii, De-Hua Chui, Keiro Shirotani and Takeshi Tabira ................................................. 209

Etiological roles of A~ and carboxyl terminal peptide fragments of amyloid precursor protein in Alzheimer disease Yoa-Hun Suh, Hye-Sun Kim, Cheol Hyoung Park, li-Heui Seo, lean-Pya Lee, Sung-lin leong, Sung-Soo Kim, lun-Ho Lee, Se Hoon Choi, Keun-A Chang, long-Cheol Rah and Sung-Su Kim ..................................... 217

Amyloid ~-protein granules in glial cells in Alzheimer's disease brain Haruhiko Akiyama, Hiromi Kondo, Eiko Tanno and Kenji Ikeda ............... 225

Amyloid ~ induces phosphorylation and translocation of MARCKS through tyrosine kinase-activated PKC-o signaling pathway in microglia Masamichi Nakai, Satoshi Tanimukai, Keiko Yagi, Naoaki Saito, Hiroshi Hasegawa, Akira Terashima and Chikako Tanaka .......................... 229

VIII Table of contents

Amyloid ~-protein accumulation in the human brain during aging Maho Morishima-Kawashima and Yasuo lhara ............................ 233

Molecular mechanisms underlying initiation of amyloid fibril formation Katsuhiko Yanagisawa .............................................. 241

Catabolism of amyloid-~ peptide in brain parenchyma Takaomi C. Saido and Nobuhisa Iwata .................................. 249

Diagnosis and therapeutics of dementia

Lessons in familial Alzheimer's disease Martin N. Rossor, John C. Janssen, Nicholas C. Fox, Richard J. Harvey, John Stevens and Elizabeth K. Warrington ............................... 259

Biological markers for differential diagnosis of Alzheimer's disease and related disorders Masatoshi Takeda, Takashi Kudo, Yu Nakamura, Toshihisa Tanaka, Takashi Nishikawa, Kazuhiro Shinosaki and Tsuyoshi Nishimura .............. 267

Dietary factors and the risk of Alzheimer's disease: a low fish consumption and a relative deficiency of (0-3 polyunsaturated fatty acids Akira Ueki, Mieko Otsuka, Satosi Sasaki, Yoshio Nanba, Yasuyoshi Ouchi and Kazuhiko Ikeda ................................................ 275

Risk factors for dementia Shigenobu Nakamura, Hirofumi Maruyama, Hiromasa Toji, Hideshi Kawakami, Michiko Yamada and Yasuyo Mimori .......................... 279

New therapeutic approaches to Alzheimer's disease Toshitaka Nabeshima and Kiyofumi Yamada .............................. 287

Subject index ..................................................... 295

IX

List of contributors

Haruhiko Akiyama, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan; e-mail: akiyama@prit.go.jp

Anja Leona Biere, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA

Jacek Biernat, Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, D-22603 Hamburg, Germany

Thomas D. Bird, Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA 98108, USA

Lawrence F. Cahill , Department of Neurobiology and Behavior and Center for the Neurobiology of Learning and Memory, University of California, Irvine, CA 92697-3800, USA; e-mail: lfcahill@uci.edu

Keun-A Chang, Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University and Biomedical Brain Research Center, NIH, Seoul 110-799, Korea

Se Hoon Choi, Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University and Biomedical Brain Research Center, NIH, Seoul 110-799, Korea

De-Hua Chui, Department of Demyelinating Disease and Aging, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan

Martin Citron, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA; e-mail: mcitron@amgen.com

Ian D'Souza, Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA 98108, USA

John E. Duda, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3600 Spruce St., 3fd Floor, Malony, PA 19104, USA; e-mail: johnduda@mail.med.upenn.edu

x List of contributors

Nicholas C. Fox, Dementia Research Group, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London WCIN 3BG, UK

Kohji Fukunaga, Department of Pharmacology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan

Michel Goedert, Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK; e-mail: mb@mrc-lmb.cam.ac.uk

Richard J. Harvey, Dementia Research Group, Institute of Neurology, Hiroshi Hasegawa, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan

Masato Hasegawa, Department of Neuropathology and Neuroscience, Graduate SchoolofPhar­maceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Takeshi Hashimoto, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan

Toshiyuki Honda, Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

Ming Hong, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3600 Spruce St., 3rd Floor, Malony, PA 19104, USA

Yasuo lhara, Department of Neuropathology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; e-mail: yihara@m.u-tokyo.ac.jp

Kazuhiko Ikeda, Department of Ultrastructure, Tokyo Metropolitan Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan; e-mail: kazikeda@artemis.prit.go.jp

Kenji Ikeda, Tokyo Institute of Psychiatry, 2-1-8, Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan

Kazunori Imaizumi, Department of Anatomy and Neuroscience, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan, Japan

Takeshi Ishihara, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3600 Spruce St., 3rd Floor, Malony, PA 19104, USA

List of contributors XI

Yoshinori Itoh, Department of Internal Medicine, Yokufukai Geriatric Hospital, Tokyo 168-0071, Japan

Nobuhisa Iwata, Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; e-mail: iwatan@brain.riken.go.jp

Takeshi Iwatsubo, Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-0033, Japan; e-mail: iwatsubo@mol.f.u-tokyo.ac.jp

John C. Janssen, Dementia Research Group, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK

Sung-Jin Jeong, Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University and Biomedical Brain Research Center, NIH, Seoul 110-799, Korea

Yuka Jinno, Department of Clinical Neuroscience and Psychiatry, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Taiichi Katayama, Department of Anatomy and Neuroscience, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Hideshi Kawakami, Third Department of Internal Medicine, Hiroshima University School of Medicine, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan

Toshio Kawamata, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan; e-mail: kawamata@hiabcd.go.jp

Hye-Sun Kim, Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University and Biomedical Brain Research Center, NIH, Seoul 110-799, Korea

Sung-Soo Kim, Department of Pharmacology, College of Medicine, Kang Won National University, Korea; e-mail: kssly@netian.com

Sung-Su Kim, Department of Anatomy, College of Medicine, Chung Ang University, Korea; e-mail: sungsu@cau.ac.kr

Jun-Ho Lee, Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University and Biomedical Brain Research Center, NIH, Seoul 110-799, Korea

XII List of contributors

Yasumasa Kokubo, Department of Neurology, Mie University School of Medicine, 2-174 Edobashi, Tsu 514-8507, Japan

Osamu Komure, Department of Neurology, Utano National Hospital, 8 Ondoyama-cho, Narutaki Ukyo-ku, Kyoto 616-8255, Japan

Hirorni Kondo, Tokyo Institute of Psychiatry, 2-1-8, Karnikitazawa, Setagaya-ku, Tokyo 156-8585, Japan

Satoshi Kotorii, Department of Demyelinating Disease and Aging, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan

Takashi Kudo, Department of Clinical Neuroscience and Psychiatry, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; e-mail: kudo@psy.med.osaka-u.ac.jp

Sadako Kuno, Department of Neurology, Utano National Hospital, 8 Ondoyama-cho, Narutaki Ukyo-ku, Kyoto 616-8255, Japan

Shigeki Kuzuhara, Department of Neurology, Mie University School of Medicine, 2-174 Edobashi, Tsu 514-8507, Japan; e-mail: kuzuhara@clin.medic.rnie-u.ac.jp

Jean-Pyo Lee, Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University and Biomedical Brain Research Center, NIH, Seoul 110-799, Korea

Jun-Ho Lee, Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University and Biomedical Brain Research Center, NIH, Seoul 110-799, Korea

Virginia M.-Y. Lee, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3600 Spruce St., 3rd Floor, Malony, PA 19104, USA; e-mail: vmylee@mail.med.upenn.edu

Jie Liu, Department of Pharmacology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan

Jean-Claude Louis, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA

Kiyoshi Maeda, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan

List of contributors XIII

Eckhard Mandelkow, Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, D-22603 Hamburg, Germany; e-mail: mand@mpasmb.desy.de

Eva-Maria Mandelkow, Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, D-22603 Hamburg, Germany

Hirofurni Maruyama, Third Department of Internal Medicine, Hiroshima University School of Medicine Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan

Naomi Matoh, Laboratory of Molecular Clinical Chemistry, Institute for Chemical Research, Kyoto University, Gokasho Uji, Kyoto 6II-00II, Japan; e-mail: naomi@scl.kyoto-u.ac.jp

Masaaki Matsushita, Department of Neuropathology, Tokyo Metropolitan Institute of Psychiatry, Tokyo 156-0057, Japan

Edith G. McGeer, Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, B.C. V6T lZ3, Canada

Patrick L. McGeer, Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, B.C., V6T lZ3, Canada; email: mcgeerpl@interchange.ubc.ca

Yasuyo Mimori, Third Department of Internal Medicine, Hiroshima University School of Medicine Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan

Eishichi Miyamoto, Department of Pharmacology, Kumamoto University School of Medi­cine, 2-2-1 Honjo, Kumamoto 860-08 II , Japan; e-mail: emiyamot@gpo.kumamoto-u.ac.jp

Koho Miyoshi, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan

Hirdehiro Mizusawa, Department of Neurology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan

Etsuro Mori, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan; e-mail: mori@hiabcd.go.jp

Hiroshi Mori, Department of Neuroscience, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan; e-mail: mori@med.osaka-cu.ac.jp

Maho Morishima-Kawashima, Department of Neuropathology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; e-mail: maho@m.u­tokyo.ac.jp

XIV List of contributors

Hideyuki Mukai, Department of Biology, Faculty of Science, Kobe University, Kobe 654, Japan

Dominique Muller, Department of Pharmacology, Centre Medical Universitaire, Universite de Geneve, Faculte de Medecine, CH 1211 Geneve 4, Switzerland

Ohoshi Murayama, Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

Toshitaka Nabeshima, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8560, Japan; e-mail: tnabeshi@med.nagoya-u.ac.jp

Masamichi Nakai, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan; e-mail: nakai@hiabcd.go.jp

Shigenobu Nakamura, Third Department of Internal Medicine, Hiroshima University School of Medicine Kasumi 1-2-3, Minamiku, Hiroshima 734-8551 Japan; e-mail: nakamura@mcai.med.hiroshima-u.ac.jp

Yu Nakamura, Department of Clinical Neuroscience and Psychiatry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Yuka Nakano, Department of Social and Environmental Medicine, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Yoshio Nanba, Department of Geriatric Medicine, Graduate School of Medicine, Tokyo Uni­versity, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 Japan; e-mail: ynanba-tky@umin.ac.jp

Linda Narhi, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA

Yugo Narita, Department of Neurology, Mie University School of Medicine, 2-174 Edobashi, Tsu 514-8507, Japan

Takashi Nishikawa, Department of Clinical Neuroscience and Psychiatry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Tsuyoshi Nishimura, Department of Human and Cultural Sciences, Koshien University, Japan

Yasutomi Nishizuka, Biosignal Research Center, Kobe University, 1-1 Rokkoudai-cho, Nada-ku, Kobe 657-8501, Japan; e-mail: nisizuka@kobe-u.ac.jp

List of contributors xv

Taketoshi Ono, Department of Physiology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan; e-mail: onotake@ms.toyama-mpu.ac.jp

Yoshitaka Ono, Department of Biology, Faculty of Science, Kobe University, Kobe 654, Japan

Eiichi Otomo, Department of Internal Medicine, Yokufukai Geriatric Hospital, Tokyo 168-0071, Japan

Mieko Otsuka, Department of Neurology, Omiya Medical Center, Jichi Medical School, 1-847 Amanuma-cho, Omiya City, Saitama 330-8503, Japan; e-mail: motsuka@omiya.jichi.ac.jp

Yasuyoshi Ouchi, Department of Geriatric Medicine, Graduate School of Medicine, Tokyo University, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; e-mail: bxr05600@nifty.ne.jp

Cheol Hyoung Park, Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University and Biomedical Brain Research Center, NIH, Seoul 110-799, Korea

Parvoneh Poorkaj, Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA 98108, USA

Jong-Cheol Rah, Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University, and Biomedical Brain Research Center, NIH, Seoul 100-799, Korea

Martin N. Rossor, Dementia Research Group, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London WCIN 3BG, UK; e-mail: m.rossor@dementia.ion.ucl.ac.uk

Naruhiko Sahara, Department of Neuroscience, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan; e-mail: nsahara@med.osaka-cu.ac.jp

Takaomi C. Saido, Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; e-mail: email:saido@brain.riken.go.jp

Naoaki Saito, Biosignal Research Center, Kobe University, Rokkodai, Nada-ku, Kobe 657-0013, Japan

Niu San-Yu, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan

XVI List of contributors

Ryogen Sasaki, Department of Neurology, Mie University School of Medicine, 2-174 Edobashi, Tsu 514-8507, Japan; e-mail: stssasak@east.ncc.go.jp

Satosi Sasaki, Department of Epidemiology, National Cancer Research Center, 6-5-1 Kashiwanoha, Kashiwa City, Chiba 227-8577, Japan

Naoya Sato, Department of Anatomy and Neuroscience, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Shinji Sato, Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

Carlos A. Saura, Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, IL 60637, USA

Gerard D. Schellenberg, Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, 1660 S. Colombian Way Seattle, Seattle WA 98108-1597, USA; e-mail: zachdad@u.washington.edu

Yuko Segawa, Department of Clinical Neuroscience and Psychiatry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Dennis J. Selkoe, Department of Neurology and Program in Neuroscience, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, 77, Ave. Louis Pasteur, HIM 730, Boston, MA 02115-5716, USA

Ji-Heui Seo, Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University and Biomedical Brain Research Center, NIH, Seoul 11 0-799, Korea

Kazuhiro Shinosaki, Department of Clinical Neuroscience and Psychiatry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Keiro Shirotani, Department of Demyelinating Disease and Aging, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan

Nobuyuki Sodeyama, Department of Neurology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan

Karsten Stamer, Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, D-22603 Hamburg, Germany

List of contributors XVII

John Stevens, Department of Radiology, The National Hospital for Neurology and Neurosurgery, Queen Square, London WCIN 3BG, UK

Peter H. St George-Hyslop, Department of Medicine, Division of Neurology, The Toronto Hospital, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada; e-mail: p.hyslop@utoronto.ca

Naomi Suematsu, Department of Pathology, Yokufukai Geriatric Hospital, Tokyo 168-0071, Japan

Yoo-Hun Suh, Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University and Biomedical Brain Research Center, NIH, Seoul 110-799, Korea; e-mail: yhsuh@plaza.snu.ac.kr.

Xiaoyan Sun, Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

Takeshi Tabira, Department of Demyelinating Disease and Aging, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan

Keikichi Takahashi Department of Demyelinating Disease and Aging, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan; e-mail: takahasi@ncnp.go.jp

Junichi Takamatsu, Division of Clinical Research, Kikuchi National Hospital, 208 Fukuhara Goushi-cho, Kikuti-gun, Kumamoto 861-1116, Japan

Akihiko Takashima, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; e-mail: kenneth@brain.riken.go.jp

Junji Takeda, Department of Social and Environmental Medicine, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Masatoshi Takeda, Department of Clinical Neuroscience, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka 565-0871, Japan; e-mail: mtakeda@psy.med.osaka-u.ac.jp

Masanori Takehashi, Laboratory of Molecular Clinical Chemistry, Institute for Chemical -Research, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan; e-mail: takehashi @scl.kyoto-u.ac.jp

XVIII List of contributors

Ryoi Tamura, Department of Physiology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan; e-mail: rtamura@ms.toyama-mpu.ac.jp

Chikako Tanaka, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan; e-mail: chikako@hiabcd.go.jp

Seigo Tanaka, Laboratory of Molecular Clinical Chemistry, Institute for Chemical Research, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan; e-mail: seigo@scl.kyoto-u.ac.jp

Toshihisa Tanaka, Department of Clinical Neuroscience and Psychiatry, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka 565-0871, Japan

Taizo Taniguchi, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan

Satoshi Tanimukai, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan

Eiko Tanno, Tokyo Institute of Psychiatry, 2-1-8, Kamikitazawa, Setagaya-ku, Tokyo 156-8585,Japan

Akira Terashima, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan

Gopal Thinakaran, Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, IL 60637, USA; e-mail: gopal@uchicago.edu

Masaya Tohyama, Department of Anatomy and Neuroscience, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Hiromasa Toji, Third Department of Internal Medicine, Hiroshima University School of Medicine Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan

Taisuke Tomita, Department of Neuropathology and Neuroscience, Graduate School of Phar­maceutical Sciences, University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-0033, Japan

Takami Tomiyama, Department of Neuroscience, Osaka City University Medical School, 1-4-3 Asahimachi Abeno-ku, Osaka 545-8585, Japan; e-mail: tomi@med.osaka-cu.ac.jp

Bernhard Trinczek, Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, D-22603 Hamburg, Germany

List of contributors XIX

John Q. Trojanowski Center for Neurodegenerative Disease Research, Department of Patho­logy and Laboratory Medicine, University of Pennsylvania School of Medicine, 3600 Spruce St., 3rd Floor, Malony, PA 19104, USA; e-mail: trojanow@mail.med.upenn.edu

Kunihiro Ueda, Laboratory of Molecular Clinical Chemistry, Institute for Chemical Research, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan; e-mail: ueda@scl.kyoto-u.ac.jp

Akira Ueki, Department of Neurology, Omiya Medical Center, Jichi Medical School, 1-847 Amanuma-cho, Omiya City, Saitama 330-8503 Japan; e-mail: uekia@omiya.jichi.ac.jp

Elizabeth K. Warrington, Dementia Research Group, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London WCIN 3BG, UK

Jette Wypych, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA

Weiming Xia, Department of Neurology and Program in Neuroscience, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, 77, Ave. Louis Pasteur, HIM 730, Boston, MA 02115-5716, USA; e-mail: xia@cnd.bwh.harvard.edu

Keiko Yagi, Biosignal Research Center, Kobe University, Rokkodai, Nada-ku, Kobe 657-0013, Japan, and Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe 658-8558, Japan

Kiyofumi Yamada, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8560, Japan; e-mail: k-yamada@med.nagoya-u.ac.jp

Masahito Yamada, Department of Neurology, Kanazawa University School of Medicine, 13-1 Takara-mach, Kanazawa 920-8640, Japan; e-mail: m-yamada@med.kanazawa-u.ac.jp

Michiko Yamada, Radiation Effects Research Foundation, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan

Katsuhiko Yanagisawa, Department of Dementia Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu 474-8522, Japan; e-mail: katuhiko@nils.go.jp

Koji Yasojima, Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, B.c. V6T lZ3, Canada

Minoru Yasuda, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan; e-mail: yasuda@hiabcd.go.jp

xx List of contributors

Bin Zhang, The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3600 Spruce St., 3rd Floor, Malony, PA 19104, USA

Preface

The lengthening survival time of populations around the world is pushing dementia into the forefront of medicine. The chapters in this timely volume are the official record of papers presented at the International Symposium on Dementia held in Kobe, Japan, September 11-13,1999. DoctorYasuo Ihara of the Program Committee, and Doctors Chikako Tanaka and Toshio Kawamata of the Organizing Committee masterfully put together a Symposium that gives a comprehensive picture of dementia, from molecular biology to therapeutics. The papers, initially for the benefit of the attendees of the Symposium, are now available to a much wider audience through this publication. As readers will discover, the chapters are written by leading authorities in their fields, each of whom has presented a clear and up-to­date summary of their particular area. The sum of this volume is much greater than the indi­vidual parts, because the reader can develop a broad understanding of dementia from the ways in which the individual papers integrate into an overview of the field.

The volume opens with chapters by Nishizuka and McGeer et aI., which deal with the phenomena of membrane lipid signaling and neuroinflammation. Although these are impor­tant to dementia, they have implications in broader fields of medicine. The next section, deal­ing with memory and its impairment, has chapters by Cahill on long-term memory, Mori on amygdala damage, Tamura and Ono on the hippocampus and Miyamoto et ai. on kinases in hippocampal long-term potentiation. The volume then turns to pathogenesis. There are eight chapters involving the protein tau which aggregates to cause neuronal degeneration in Alzheimer disease and other degenerative neurological disorders where neurofibrillary tan­gles and other tau deposits occur. These chapters include one on transgenic mice by Ishihara et aI., two on tau mutations by Schellenberg et ai. and Yasuda et aI., one on the ALS-PDC complex of the Kii peninsula by Kuzuhara et aI., one on an apparently new NFf entity by Yamada et ai. and three on cellular pathology by Mandelkow et aI., Sahara et al. and Kawamata et ai. The next section contains three chapters on dementia related to synuclein by Duda et aI., Tanaka et ai. and Citron et ai. The role of the presenilins and amyloid pre­cursor protein in Alzheimer disease is next covered in a series of thirteen chapters. These include seven on the presenilins by St. George-Hyslop, Thinakaran et aI., Iwatsubo and Tomita, Xia and Selkoe, Kudo et aI., Takashima et ai. and Takahashi et ai. They are followed by six chapters on various aspects of beta-amyloid peptide by Suh et aI., Akiyama et aI., Nakai et aI., Morishima-Kawashima and Ihara, Yanagisawa, and Saido and Iwata. Finally, there are five chapters on the diagnosis and therapeutics of dementia by Rossor et aI., Takeda et aI., Ueki et aI., Nakamura et aI., and Nabeshima and Yamada.

The reader will find a rich intellectual array in this volume. Key aspects of a vast and scattered literature have been neatly drawn together to provide an integrated view of one of the major medical problems of our time.

Patrick L. McGeer