Alzheimer’s Disease: Advances in Genetics, Molecular and Cellular Biology

291 Pages·2007·3.42 MB·English

by  Lars Bertram MD (auth.)

ALZHEIMER’S DISEASE
Advances in Genetics,
Molecular and Cellular Biology
ALZHEIMER’S DISEASE
Advances in Genetics,
Molecular and Cellular Biology
Editedby
Sangram S. Sisodia
TheUniversityofChicago,IL
and
Rudolph E. Tanzi
Massachusetts GeneralHospitalandHarvardMedicalSchool
Cover:
Atomic force microscopy images of human chromosomes
Courtesy of Dr. Stefan Thalhammer, GSF-Forschungszentrum for Environment and Health,
Institute of Radiation Protection, AG Nanoanalytics, Ingolstädter Landstra(cid:533)e 1 85764
Oberschleissheim, Germany
Thioflavin S image of plaques and tangles
Courtesy of Dr. Robert D. Terry, Professor Emeritus, Departments of Pathology and
Neurosciences,University of California, San Diego, USA
Library of Congress Control Number: 2006926955
ISBN-10: 0-387-35134-5 e-ISBN-10: 0-387-35135-3
ISBN-13: 978-0-387-35134-6 e-ISBN-13: 978-0-387-35135-3
Printed on acid-free paper.

(cid:164) 2007 Springer Science+Business Media, LLC
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Table of Contents
Introduction vii
Chapter1: TheGeneticsofAlzheimer’sDisease
LarsBertram 1
Chapter2: APPBiology,ProcessingandFunction
GopalThinakaranandEdwardH.Koo 17
Chapter3: TheBiologyofthePresenilinComplexes
TomokoWakabayashi,TakeshiIwatsuboandBartDeStrooper 35
Chapter4: β-secretase:PhysiologicalRoleandTargetValidation
FionaM.Laird,MohamedH.Farah,Hey-KyoungLee,
AlenaV.Savonenko,DonaldL.PriceandPhilipC.Wong 59
Chapter5: CognitiveImpairmentinTransgenicAβ andTauModels
ofAlzheimer’sDisease
KarenH.Ashe 77
Chapter6: Cholesterolandβ-Amyloid
HenriJ.HuttunenandDoraM.Kovacs 93
Chapter7: Aβ StructureandAggregation
CharlesGlabeandAshleyI.Bush 113
Chapter8: SignalingMechanismsthatMediateAβ Induced
NeuronalDysfunction
CarlW.CotmanandJorgeBusciglio 133
Chapter9: BetaAmyloidandExcitatorySynapses
RobertoMalinow,HelenHsiehandWeiWei 151
vi TableofContents
Chapter10: Aβ Degradation
MalcolmLeissringandTakaomiC.Saido 157
Chapter 11: Role of Aβ Transport and Clearance in the Pathogenesis
andTreatmentofAlzheimer’sDisease
DavidM.HoltzmanandBerislavZlokovic 179
Chapter12: TauGeneMutationsinFTDP-17Syndromes
MatthewJ.Winton,JohnQ.TrojanowskiandVirginiaM-Y.Lee 199
Chapter13: AnimalModelsofTauopathy
KarenDuff,PavanKrishnamurthy,EmmanuelPlanel
andMichaelHutton 215
Chapter14: TauandAxonalTransport
E.-M.Mandelkow,E.ThiesandE.Mandelkow 237
Chapter15: GrowthFactorsinAlzheimer’sDisease
A.H.NagaharaandM.H.Tuszynski 257
Index 279
Introduction
Roughly one hundred years ago at a meeting of Bavarian psychiatrists,
Dr. Alois Alzhiemer presented the intriguing case of his patient, Auguste
D., a 51 year-old female admitted to the local asylum with presenile de-
mentia. He would argue that specific lesions in and around neurons were
responsible for dementia. In the ensuing decades, studies of her disorder,
which would be named Alzheimer’s disease (AD), were largely limited to
descriptive neuropathological and psychological assessment of this disease
withlittleunderstandingofthemolecularandcellularmechanismsunderlying
neurodegeneration and dementia. This would change in the 1980’s when the
protein components of the major neuropathological hallmarks of the disease,
senile plaques (and cerebral blood vessel amyloid) and neurofibrillary tangles
were first determined. The identification of the β-amyloid protein (Aβ) and
themicrotubule-associatedtauproteinasthemaincomponentsofplaquesand
tangles, respectively, would pave the way for the molecular genetic era of
AD research. By the late-1980’s, the genes encoding the β-amyloid precursor
protein (APP) and tau (MAPT) were identified and would subsequently be
shown to harbor autosomal dominant mutations causing early-onset familial
AD and frontal temporal dementia (FTD), respectively. Later, in the early
1990’stheε4variantoftheapoliproteinEgene(APOE)wouldbefoundtobe
associatedwithincreasedriskforlate-onsetAD.Fundamentaldifferenceswere
soon noted between these two AD genes: APP and APOE. First, while APP
mutations caused AD with virtual certainty, the APOE-ε4 variant increased
susceptibilityfor,butnotguaranteeonsetofAD.Second,whileAPPmutations
increased the generation of the neurotoxic peptide, Aβ42, in brain, APOE-
ε4 affected aggregation of Aβ into fibrils and its clearance from brain. In
1995, two more familial AD genes, presenilin 1 and 2 (PSEN1, PSEN2) were
identified, and mutations in MAPT were linked to frontal temporal dementia.
Thus,by1995,thestagewassetformolecularstudiesofage-relateddementias
withAPP,presenilin1and2,APOE,andtauplayingthemajorroles.
With the turn of the 21st century, the search for novel AD and FTD genes
wouldcontinue,utilizinghigh-throughput,chip-basedgenotypingtechnologies
viii Introduction
facilitated by the expansive DNA variant databases and the advent of the
HapMap. However, the vast majority of studies addressing the molecular
mechanisms underlying dementia would continue to focus on characterizing
the five genes already firmly implicated in the etiology and pathogenesis of
these dementing disorders. These five genes and the molecules they encode
are absolutely critical pieces of the puzzle of age-related dementias, however,
exactly how and where they fit into the puzzle remains a subject of intensive
investigation. In mathematical terms, these molecules can be considered as
the “givens” in the incredibly complex equation underlying the etiology and
pathogenesis of AD and FTD. Studies of these molecules have not only
elucidated the genetic, molecular, and biochemical basis of AD and FTD, but
have already begun to guide the design and development of novel ways to
diagnose, treat, and prevent these diseases. The contributors to Alzheimer’s
Disease: Advances in Genetics, Molecular and Cellular Biology cover the
remarkable progress that is being made in studies of these and other relevant
molecules and the cellular processes in which they participate. The findings
described in these chapters have not only enhanced our understanding of the
molecular basis of dementia, but have also provided a firm foundation for
translational studies that will hopefully serve to take these findings from the
benchtoptothebedside.
Despitetheincredibleamountofdatathathasbeengarneredbystudyingthe
fourestablishedADgenes,wealsoknowthattheylikelyaccountforonly30%
of the genetic variance involved in AD. In the Chapter 1, Bertram covers the
efforts and challenges in identifying the remaining AD genes. All four of the
establishedADgenessupporttheamyloidhypothesisofAD,whichmaintains
that the accumulation of Aβ in the brain is the key pathogenic event in AD.
The accumulation of Aβ is the net result of production of the peptide versus
it’s degradation and clearance from brain. The molecular and cell biological
studies of the known FAD genes including their effect on Aβ production, are
summarizedinchaptersbyThinakaranandKoo(APP),andWakabayashietal
(PSEN1andPSEN2).Theroleoftheβ-secretase(BACE)inADpathogenesis
andAβ productionisencapsulatedinthechapterbyLairdet.al.Huttunenand
Kovacs summarize the role of cholesterol and cholesterol pathway enzymes
in regulating the Aβ generation. With regard to Aβ clearance, Holtzman and
Zlokovic discuss the processes by which Aβ is transported out of the brain,
including the role of APOE, while Leissring and Saido summarize the means
bywhichAβ isdegradedinbrain.DegradationofAβ issignificantlyhampered
byitsconversionfrommonomertooligomericassembliesandamyloidfibrils.
TheseprocessesaredescribedinthechapterbyGlabeandBush.Withregardto
the neurotoxic effects of Aβ, the potentially detrimental effects of the peptide
on neuronal signaling are summarized by Cotman and Busciglio, while the in
vivo effects of Aβ and tau in transgenic mouse models, are presented in the
Introduction ix
chapter by Ashe. On the other side of the coin, Malinow covers the possible
normalphysiologicalrolesofAβ inmodulatingactivityofexcitatorysynapses.
Several excellent chapters on tau, tangles, and the FTDs are also included.
Winton et al. provide a summary of the MAPT mutations involved in FTD,
while Duff et al. provide an overview of mouse models of FTD and other
tauopathies. The Mandelkows discuss the normal and pathogenic roles of the
tauproteininaxonaltransport.Finally,NagaharaandTuszynskisummarizethe
roleofgrowthfactorsinADandprospectsforgenetherapyusingnervegrowth
factor.
The Editors of Alzheimer’s Disease: Advances in Genetics, Molecular and
Cellular Biology congratulate the authors for their outstanding contributions,
and for providing exciting, comprehensive and up-to-date summaries of the
most important recent advances in the genetic, molecular, biochemical, and
cell biological studies of AD. The last five years have witnessed remarkable
progress in all of these areas, and there have certainly been some surprises
along the way – Aβ playing a role in modulating synaptic transmission
(Malinow); BACE1 contributing to learning and memory processes (Laird et
al.); and, neurofibrillary tangles not appearing to cause cognitive deficits in
mice (Ashe). Isaac Asimov may have put it best when he said: “The most
exciting phrase to hear in science, the one that heralds new discoveries, is not
‘Eureka!’ (I found it!) but ‘That’s funny...”. Biotechnology and pharmaceuti-
cal companies continue efforts to convert the genetic, molecular, cellular and
neurobiologicalfindingsdescribedinthesechaptersintonoveltherapeuticsfor
treating and preventing AD, FTD, and other dementing disorders of late life.
Weonlyhopethattheadvancesdescribedinthesepageswillhelptoaccelerate
this process of rational drug discovery and soon serve to extend and enhance
thementalhealthspanofourburgeoningelderlypopulation.
Dr.RudolphE.Tanzi Dr.SangramS.Sisodia
HarvardMedicalSchool UniversityofChicago
Chapter 1
The Genetics of Alzheimer’s Disease
LarsBertram,MD
GeneticsandAgingResearchUnit
DepartmentofNeurology
MassGeneralInstituteforNeurodegenerativeDiseases(MIND)
MassachusettsGeneralHospital
11416thStreet,Charlestown,MA,02129
Email:[email protected]
1. Introduction
Alzheimer’sdisease(AD),themostcommonformofage-relateddementia,
is characterized by progressive and insidious neurodegeneration of the central
nervoussystemthateventuallyleadstoagradualdeclineofcognitivefunction
anddementia.TheprincipalneuropathologicalfeaturesofADarethepresence
of neurofibrillary tangles and β-amyloid (Aβ) deposited in the form of senile
plaques. Although the knowledge of disease pathophysiology still remains
fragmentary,itisnowwidelyacceptedthatinheritanceofspecificgenesplays
acriticalroleinpredisposingtoonsetand/orinmodifyingdiseaseprogression.
Infact,familialaggregationhadbeenrecognizedasaprominentcharacteristic
of AD and several other neurodegenerative disorders. More specifically, the
identificationofspecific,disease-segregatingmutationsinpreviouslyunknown
genes has directed attention to specific proteins and pathways that are now
consideredcriticalinthepathogenesisofthesediseases(e.g.mutantβ-amyloid
precursor proteins that cause AD; mutant α-synuclein that cause Parkinson’s
disease;ormutanttauvariantsthatcausefrontotemporaldementia(FTD)with
parkinsonism;forreviewsee:BertramandTanzi,2005).
Another common feature observed in many neurodegenerative diseases is
a dichotomy of familial (rare) vs. seemingly non-familial (common) forms.
Thelatterarealsofrequentlydescribedas“sporadic”or“idiopathic”,although
thereisagrowingbodyofevidencesuggestingthatalargeproportionofthese