Emerging Drugs and Targets for Alzheimer's Disease Volume 1: Beta-Amyloid, Tau Protein and Glucose Metabolism

343 Pages·2010·6.328 MB·English

by  Ana Martínez;

RSC Drug Discovery
Edited by Ana Martinez
Emerging Drugs and Targets for
Alzheimer’s Disease
Volume 1: Beta-Amyloid, Tau Protein and
Glucose Metabolism
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Emerging Drugs and Targets for Alzheimer’s Disease
Volume 1: Beta-Amyloid, Tau Protein and Glucose Metabolism
RSC Drug Discovery Series
Editor-in-cheif:
ProfessorDavidThurston,LondonSchoolofPharmacy,UK
SeriesEditor:
DrDavidFox,PfizerGlobalResearchandDevelopment,Sandwich,UK
ProfessorSalvatoreGuccione,UniversityofCatania,Italy
ProfessorAnaMartinez,InstitutodeQuimicaMedica-CSIC,Spain
DrDavidRotella,WyethResearch,USA
AdvisortotheBoard:
ProfessorRobinGanellin,UniversityCollegeLondon,UK
TitlesintheSeries:
1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups: Impact of the
BuildingBlocksofMedicinalChemistryonADMET
2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1: Beta-Amyloid,
TauProteinandGlucoseMetabolism
3: EmergingDrugsandTargetsforAlzheimer’sDisease;Volume2:NeuronalPlasti-
city,NeuronalProtectionandOtherMiscellaneousStrategies
Howtoobtainfuturetitlesonpublication:
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Emerging Drugs and Targets for
Alzheimer’s Disease
Volume 1: Beta-Amyloid, Tau Protein and
Glucose Metabolism
Edited by
Ana Martinez
Instituto de Quimica Medica-CSIC, Madrid, Spain
RSCDrugDiscoverySeriesNo.2
ISBN: 978-1-84973-063-1
ISSN: 2041-3203
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rRoyalSocietyofChemistry2010
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Foreword
It is a great honour to have been asked to write the foreword to this book in
which several distinguished experts in the field have commented on possible
therapeutic approaches for the treatment of Alzheimer’s disease (AD) and, in
some cases, for the possible side effects of those treatments.
Onehundredyearsago,thefirstpatientwiththisdiseasewasdescribed,1but
during this time we have been unable not only to cure but even to prevent the
disease. However, during the last 25 years knowledge of several molecular
aspectsofthediseasehasdramaticallyincreased.InfamilialAD,weknowthat
theoriginoftheneurodegenerationisaconsequenceofmutationsinoneofthe
threefollowinggenes:app,ps-1andps-2.2APP(amyloidprecursorprotein)is
the product of app,3 and ps-1 and ps-2 code for the proteins, presenilin-1 and
presenilin-2.4FromthepioneeringworkofGlennerandWang,5weknowthat
themaincomponentofsenileplaques,foundinthebrainofAlzheimerpatients
isafragment(thebetaamyloidpeptide)ofAPP.Itiswellknownthatthemain
componentoftheotheraberrantstructurefoundinthebrainofthosepatients,
neurofibrillary tangles, is the cytoskeletal protein tau, modified by hyperpho-
sphorylation.6 The kinases involved in that aberrant phosphorylation and the
aggregationoftauhavebeenalsostudied.6–8Lessisknownabouttheoriginof
sporadic Alzheimer disease, but there are some risk factors, like aging (that
could promote oxidative damage), or the presence of a specific isoform of the
protein ApoE, involved in cholesterol transport in the nervous system.9
On the other hand, mutations in ps-1 gene could affect glial cells, like
microglia, inducing an aberrant activation of those cells.10 That activation
could have some consequences, such as aberrant induction of proliferation of
neuronal precursors and inflammation. Indeed, AD can be defined as a CNS
disorder with an inflammatory component.
OtherstudieshavesuggestedthatADisaninsulin-resistancediseaseorthat
factors related to insulin could act as putative therapeutic agents for the dis-
order.11 Other changes in the amount of growth factors, or changes in brain
metabolism, have been associated with other aspects of the disease, and, in
addition,fromthepioneerworkofDavidandMaloney,12changesinthelevel
of different neurotransmitters have been found in AD patients.
v
vi Foreword
Inspection of the web site, clinicaltrials.gov, reveals that more than two
hundred compounds are currently in clinical trials for AD treatment, and cur-
rentlytherearenobroadlyeffectiveagentsforADtreatment.Thus,theaimof
this book is to comment on emerging drugs and targets for Alzheimer disease.
Amongthosetargetsarethoseproteases(bandgsecretase)thatareinvolvedin
APPcleavage,yieldingbetaamyloidpeptide(Ab),althoughinhibitionofthese
proteins(mainlyg-secretase)couldresultindangeroussecondaryeffects.13Also,
sincedimers,dodecamers,otheroligomersandhigherpolymersofAbcouldbe
toxic for neurons,14 Ab anti-aggregates have been tested.
On the other hand, some kinases or phosphatases involved in the aberrant
phosphorylation of tau protein, the main components of NFT, have been
described as possible targets to prevent tau pathology, together with antitau
aggregates that could prevent the formation of filamentous tau polymers.
In the case of sporadic Alzheimer disease, alterations in the metabolism of
cholesterol have been studied,15 and modulation of cholesterol levels has been
suggested for the treatment of the disease.
The27chaptersofthisbookprovideabroadbasedanddeepreviewonsome
of the above-mentioned targetsfor Alzheimerdisease. In Volume 1, the initial
section considers strategies aimed at lowering Ab levels and blocking Ab
aggregation by targetting Ab secretases, or by other approaches, including
immunotherapy. This part includes six chapters, from Drs. Wolfe, Xia, Dotti
andLedesma, Soreq, McLaurin and Solomon. Therapeutictargetsfocusedon
tauproteinfollows,focusingontheregulationofitsdephosphorylation,mainly
bytaukinaseI,16,17(orGSK3),oritsdephosphorylationbyphosphataseslike
PP2A.18Thissectionincludesadiscussionoftherationalefortau-aggregation
inhibitor therapy inthe lastchapter ofthis part. The authors forthese aspects
related to tau pathology are Drs. Iqbal, Jope, Martı´nez,Hovensand Wischik.
The third part of the book is related to neuron glucose metabolism as a
possible target, discussing the possibility of AD being an insulin-resistance
disease, about the possible use of insulin-like growth factor 1 as an AD ther-
apeutic or the use of ketone bodies in the potential treatment of AD. The
authorsforthesethreechaptersareDrs.DelaMonte,TorresandHenderson.
In Volume II the first part is related to aspects of neuronal plasticity. The
possibilityforregenerationofdegeneratedbrainandtheuseofgrowthfactors
likeNGFisdiscussed.Theuseofinducedpluripotentcellsfrompatientscould
facilitatethesearchforspecificdrugsinthetreatmentofthediseaseorhowto
promotesynapticresilienceinADpatients.Theauthorsforthesechaptersare
Drs Grundke-Iqbal, Cattaneo, Sugaya and Menniti.
The second part of Volume II is related to different ways for neuronal pro-
tection, trying to prevent oxidative damage, microtubule breakdown or
inflammatory processes. Four chapters are dedicated to those subjects from
Drs. Smith, Ghozes, Vallano and Heneka.
The final section of Volume II is entitled ‘‘Miscellaneous targets and stra-
tegies’’ and, as indicated by the title, tries to look for additional solutions
beyond the targets previously described. Five chapters are dedicated to this
topic from Drs. Lezoualc’h, Ridell, Melchiorre, Nawrot and Kennedy.
Foreword vii
Insummary,awidevarietyofconceptuallydistinctapproachesarepresented
in an attempt to treat or prevent Alzheimer disease, a disease discovered 100
years ago whose incidence has dramatically increased since that time. Hope-
fully, memories of this dreaded disease will disappear before the 200th anni-
versary of its description.
Jesu´s Avila
Centro de Biologı´a Molecular ‘‘Severo Ochoa’’ (CSIC-UAM), Madrid, Spain
References
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2. D. L. Price and S. S. Sisodia, Ann. Rev. Neurosci., 1998, 21, 479.
3. C.L.Masters,G.Simms,N.A.Weinman,G.Multhaup,B.L.McDonald
and K. Beyreuther, Proc. Nat. Acad. Sci. USA., 1985, 82, 4245.
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Ikeda,H.Chi,C.Lin,G.LiandK.Holman,etal.,Nature,1995,375,754.
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M. Wisniewski, J. Biol. Chem., 1986, 261, 6084.
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Gaskell,G.W.Small,A.D.Roses,J.L.HainesandM.A.Pericak-Vance,
Science, 1993, 261, 921.
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M. Ramirez and S. S. Sisodia, Neuron, 2008, 59, 568.
11. E. Carro, J. L. Trejo, T. Gomez-Isla, D. LeRoith and I. Torres-Aleman,
Nature Med., 2002, 8, 1390.
12. P. Davies and A. J. Maloney, Lancet, 1976, 2, 1403.
13. E. Inoue, M. Deguchi-Tawarada, A. Togawa, C. Matsui, K. Arita, S.
Katahira-Tayama, T. Sato, E. Yamauchi, Y. Oda and Y. Takai, J. Cell
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14. C. Haass and D. J. Selkoe, Nature Rev., 2007, 8, 101.
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Delacourte, C. Dingwall and C. G. Dotti, EMBO Rep., 2003, 4, 1190.
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Preface
‘‘Over the next century, experts estimate that Alzheimer’s disease will be
more prevalent than AIDS, cancer and all cardiovascular diseases’’
World Health Organization
Alzheimer0s disease, the most common form of dementia, is a progressive
and neurodegenerative brain disorder that results in symptoms such as loss of
memory, impaired reasoning and changes in mood and behavior. The risk of
suffering thispathology increasessharplywithageandposesone ofthemajor
public health problems, both emotional and financial, not only to the present
society, but even more to the coming generation. The lack of a cure and an
effective form of treatment means that our current society must find effective
ways to slow the progression of Alzheimer’s disease and develop effective and
efficient strategies to meet the needs of those with this challenging disease.
Recent research advances in molecular biology and technology have pro-
vided multiple credible hypotheses around which therapeutic agents can be
developed. This book collects some of the most outstanding examples of new
drugs currently under pharmaceutical development or new targets in the vali-
dation process that will reach the Alzheimer’s drugs market over the next few
years as disease modifying drugs.
I wish to thank all the contributors to the chapters in this book for their
effortstosummarizethemostrelevantdataontheirtopicsandmainly,fortheir
faith in the project. I also extend special thanks to my colleagues Guadalupe
Mengod,CarmenGil,AnaPerez-Castillo,ManuelSarasa,JesusAvila,Khalid
IqbalandDanielPerezfortheirsupportinreviewingsomeofthechapters.My
special thanks and undying gratitude to Valle Palomo for her help with the
RSCDrugDiscoverySeriesNo.2
EmergingDrugsandTargetsforAlzheimer’sDisease
Volume1:Beta-Amyloid,TauProteinandGlucoseMetabolism
EditedbyAnaMartinez
rRoyalSocietyofChemistry2010
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
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