Table Of ContentNEUROPATHOLOGY AND
GENETICS OF DEMENTIA
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
EditorialBoard:
NATHAN BACK,State UniversityofNew YorkatBuffalo
IRUN R. COHEN.The Weizmann Institute ofScience
DAVID KRITCHEVSKY. WistarInstitute
ABELLAJTHA.N. S. Kline Institutefor PsychiatricResearch
RODOLFOPAOLETTI, UniversityofMilan
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NEUROPATHOLOGY AND
GENETICS OF DEMENTIA
Edited by
MARKUS TOLNAY
and
ALPHONSE PROBST
University 0/ Basel
Basel, Switzerland
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Library of Congress Cataloging-in-Publieation Data
Neuropathology and genetics of dementialedited by Markus Tolnay and Alphonse Probst.
p. em. - (Advanees in experimental medieine and biology; v. 487)
ISBN 978-1-4613-5461-1 ISBN 978-1-4615-1249-3 (eBook)
DOI 10.1007/978-1-4615-1249-3
I. Dementia-Pathophysiology-Congresses. 2. Dementia-Genetie
aspeets-Congresses. 3. Nervous system-Pathophysiology-Congresses. I. Tolnay,
Markus, 1962- 11. Probst, Alphonse, 1938- III. Series.
RC521 .N47 2001
616.8'3-de21
00-067413
Proceedings of the Swiss Soeiety for Neuropathology XVIIIth International Winter Meeting on Neuropathology
and Geneties of Dementia, held Mareh 23-26, 2000, in SI. Moritz, Switzerland
ISSN: 0065 2598
ISBN 978-1-4613-5461-1
©2001 Springer Science+Business Media NewYork
Originally published by Kluwer Academic/Plenum Publishers, New York in 2001
Softcover reprint of the hardcover 1s t edition 2001
10987654321
A C.l.P. reeord for this book is available from the Library of Congress
All rights reserved
No part of this book may be reprodueed, stored in a retrieval system, or transmitted in any form or by any
means, eleetronie, meehanieal, photocopying, mierofilming, recording, or otherwise, without written permission
from the Publisher
Preface
For more than 35 years the Swiss Society of Neuropathology has
organised its traditional International Winter Meeting. The main aim ofthis
venue is to bring together neuropathologists and clinicians as well as
neuroscientists interested in disease mechanisms. TheXVIIIth International
Winter Meeting was held in March 2000 in St. Moritz, Switzerland. The
topic ofthe 2000Meetingwas "NeuropathologyandGenetics ofDementia".
Aprogramme ofinvitedplenarylectures ofhigheducational value as well as
platform and poster presentations given by many participants covered the
broad spectrum ofdementing disorders. Encouraged by the high standard of
the meeting, and probably also influenced by the advent of a new
Millenniumwedecided, togetherwithKluwerAcademiclPlenumPublishers,
to publishthe Proceedings ofthe 2000Meetinginthepresentbook.
The increase of the aged population challenges social and health care
systems in industrialized societies. Maintenanceofhealthandautonomyinto
old age is a key factor, and the autonomy and independence ofold persons
crucially depend on mental health. However, neurodegenerative disorders
accompanied by dementia affect 5-10% of individuals over the age of 65,
and for the age group between 65 and 95 the prevalence of cognitive
dysfunction doubles every 5 years. With this challenge in mind, Rossor
discusses the clinical syndrome of dementia which encompasses an
enormous variety ofunderlying disorders.
Over the last few years it has become apparent that many
neurodegenerative disorders are characterised by protein misfolding and
aberrant polymerization and may therefore be viewed as "aggregation
proteopathies". Among them a substantial subset of dementing disorders,
either with or without motor dysfunction, are characterised by abundant
v
VI Preface
neuronal and/or glial accumulation ofhyperphosphorylated tau protein. The
molecular parameters of these "tauopathies" are reviewed by Delacourte.
The recentdiscovery that mutations ofthe tau genearecausativefor familial
forms offrontotemporal dementia and Parkinsonism (FTDP-17) broughtthe
"tau pathway" and the "tauopathies" to the centre stage. This extraordinary
breakthrough will be covered by Spillantini andGoedert. There isincreasing
evidence that argyrophilic grain disease is much more frequent in older
patients than previously thought. Tolnay et al. are reviewing recent
contributions to the pathology ofthis late-onsetdementing disorderinwhich
taupathology, inthe almost total absence ofamyloidbetadeposits, is almost
exclusively restricted to the limbic lobe and the amygdala. Schultz et al.
report an intriguing age-related progression of neuronal and glial tau
pathology in baboons thus rendering the baboon a potential primate model
for age-related human "tauopathies". Gotz et al. introduce transgenic mice
expressing mutated human tau as valuable animal models for reproducing
formation ofneuro- and glial fibrillary lesions.
AD is neuropathologically characterised by abundant extracellular
amyloid beta deposits (among them the neuritic plaques) and intracellular
neurofibrillary tangles. Gandy and Petanceska are reviewing the hitherto
proposed mechanisms of amyloid precursor protein (APP) trafficking and
metabolism. In additionthey focus ontherecentfindings thatestradiolmight
influence the risk or age-at-onset of AD by lowering the speed of the
accumulation of amyloid beta protein. The role of type 10 17beta
hydroxysteroid dehydrogenase in this process is reviewed by Yang and He.
In AD but also in non-demented elderly subjects the amyloid beta protein
accumulates in the walls of small cerebral blood vessels (cerebral amyloid
angiopathy; CAA). Weller and Preston present evidence for the hypothesis
that CAA results from the accumulation ofamyloid peptides in perivascular
interstitial fluid drainage pathways and that the impedence of drainage of
amyloid beta protein from the brain may contribute to the onset ofAD. The
contribution by Herzig et al. on APP transgenic mice which develop
abundant CAA is in line with this hypothesis.
Lewy bodies and Lewy neurites are hallmark lesions of Parkinson's
disease (PD) and Dementia with Lewy bodies (DLB), and the main protein
constituent of these lesions is the presynaptic protein alpha-synuclein.
Alpha-synuclein is also present in glial cytoplasmic inclusions ofmultiple
system atrophy (MSA), and therefore PD, DLB and MSAhave been lumped
under the term "alpha-synucleinopathies". Jensen and Gai review therole of
alpha-synuclein in neurodegeneration while the contributionby Ince focuses
on the relationship between AD, PD and DLB at the clinicopathological
level. Recent findings in vivo intransgenic flies and transgenicmice provide
novel perspectives to model in animals the pathophysiology ofdiseases with
Preface VB
alpha-synucleinopathy. These new aspects are covered by the contribution
by Barbieri etal.
A large number of disease-related cellular fea,tures can be detected by
ubiquitin immunohistochemistry. While for some disorders the molecular
nature of the ubiquitinated filamentous inclusions is well known, e.g.
amyloid beta protein, tau protein, alpha-synuclein and huntingtin, there is a
substantial subset ofneurodegenerative disorders for which the nature ofthe
pathological protein complexed with ubiquitin still remains unknown.
Among others, motor neuron disease, frontotemporal dementia with
inclusions of motor neuron disease type and some cases of primary
progressive aphasia and semantic dementia belong to this group of
"ubiquitindisorders". The involvementofthe ubiquitin systemin diseasesof
the nervous system will be covered by Lowe et al. Furthermore, using
ubiquitin-immunohistochemistry, Probst et al. describe a novel type of
hippocampal ubiquitinpathology inAD and Pick's disease.
Polyglutamine expansion diseases such as Huntington's disease,
spinobulbar muscular atrophy and spinocerebellar ataxia constitute a subset
of "proteopathies" in some of which there are abundant neuronal
intranuclear polyglutamine inclusions. The pathological mechanisms
underlying these disorders will bereviewedbyDevys etal.
Though most of us would associate the term dementia with old age,
dementia may also occur in the pediatric age group in a variety of
progressive neurological disorders. The contribution by Goebel and
Kohlschiitter deals with the presence of dementia in the neuronal ceroid
lipofuscinoses.
Thereader mightaskwhyinclusion bodymyositis (IBM) isincluded ina
book devoted to dementia. However, it has become apparent in the last few
years that IBM inclusions encompass a wide range ofproteins involved in
neurodegenerative dementing disorders, such as APP, tau, presenilin-l,
apolipoprotein E and prion protein. Lampe et al. are focusing on the role of
neurodegeneration-associatedproteins inIBM.
Last, but not least, the book closes with the contribution by Turner and
Schapira who critically review the evidence for the role of mitochondrial
dysfunction in a wide range ofneurodegenerative disorders and the ageing
brain.
Together with the contributors we believe that this bookwill not only be
useful to neuropathologists but also to clinicians and basic scientists
interested in the broad field ofdementia.
Markus Tolnay
AlphonseProbst
Acknowledgments
We thank the authors for their contributions, the publishers, particularly
Joanna Lawrence, for their help in the production ofthis book and Thomas
Schiirch and Michelle Pfeiffer for their photographic and administrative
help. Finally, we are grateful to Kurt Brauchli who guided us safely through
all expected,butevenmore important,unexpectedcomputerproblems.
MarkusTolnay
AlphonseProbst
IX
Contents
CANTHEPHYSICIANPREDICTTHENEUROPATHOLOGIST?
MartinN. Rossor 1
THEMOLECULARPARAMETERS OFTAUPATHOLOGY
Tau as a killerandawitness
AndreDelacourte , ,'" 5
TAUGENE MUTATIONSAND TAUPATHOLOGYIN
FRONTOTEMPORALDEMENTIAANDPARKINSONISMLINKEDTO
CHROMOSOME 17
MariaG. SpillantiniandMichelGoedert 21
ARGYROPHILIC GRAINDISEASE
Afrequent dementingdisorderin agedpatients
MarkusTolnay,AndreasU. MonschandAlphonseProbst 39
TAUPATHOLOGYINNEURONSANDGLIALCELLSOFAGED
BABOONS
ChristianSchultz, Gene B. Hubbard, KellyDelTredici,EvaBraakand
HeikoBraak 59
Xl
XII Contents
HUMANTAUTRANSGENIC MICE
Towards an animalmodelfor neuro-andglialfibrillarylesionformation
JiirgenG6tz, MarkusTolnay,RobiBarmettler,AlessandraFerrari,KurtBiirki,
MichelGoedert, AlphonseProbstandRogerM. Nitsch 71
REGULATIONOFALZHEIMERI3-AMYLOIDPRECURSOR
TRAFFICKINGAND METABOLISM
SamuelGandyandSuzanaPetanceska 85
ROLE OFTYPE 10 1713-HYDROXYSTEROIDDEHYDROGENASEIN
THE PATHOGENESISOFALZHEIMER'SDISEASE
Song-YuYang andXue-YingHe 101
THE SPECTRUMOFVASCULARDISEASEINDEMENTIA
From ischemia to amyloidangiopathy
Roy O. WellerandStephenD. Preston 111
TRANSGENICMOUSEMODELSOFCEREBRALAMYLOID
ANGIOPATHY
MartinC. Herzig, DavidT. Winkler, LaryC. WalkerandMathiasJucker 123
ALPHA-SYNUCLEIN
Axonaltramport, ligandinteractionandneurodegeneration
PoulHenningJensenand WeiPingGai 129
DEMENTIAWITHLEWYBODIES
PaulIllce 135
MOUSE MODELSOFu-SYNUCLEINOPATHYANDLEWY
PATHOLOGY
a-synuclein expression in transgenicmice
SamuelBarbieri, KatjaHofele,Karl-HeinzWiederhold, AlphonseProbst,
ClaudiaMistl, SimoneDanner, SabineKauffmann, BerndSommer,Willibrordus
Spooren, MarkusTolnay, GraemeBilbeandHermanvanderPutten 147
UBIQUITIN ANDTHEMOLECULARPATHOLOGYOF
NEURODEGENERATIVEDISEASES
James Lowe, JohnMayer,MichaelLandonandRobertLayfield 169
