A Look at AlzheimerA Look at Alzheimer’’ssDisease and TreatmentDisease and Treatment

PossibilitiesPossibilities

Laura MeckerLaura MeckerApril 24, 2007April 24, 2007

StatisticsStatistics

Currently more than 5 million people in the USCurrently more than 5 million people in the USsuffering from Alzheimersuffering from Alzheimer’’s Diseases Disease 1 in 8 over the age of 651 in 8 over the age of 65 By 2050, 11-16 million could suffer from ADBy 2050, 11-16 million could suffer from AD

Largest cause of dementiaLargest cause of dementia By 2010, $160 billion is spent on AD patientsBy 2010, $160 billion is spent on AD patients

Family out of pocket costsFamily out of pocket costs Diagnosis?Diagnosis?

SymptomsSymptoms

Dementia: failure of recent memory andDementia: failure of recent memory andintellectual functionsintellectual functions

Abstract thinkingAbstract thinking Failure of language skillsFailure of language skills Visual-spatial orientationVisual-spatial orientation JudgmentJudgment Alteration of personalityAlteration of personality

http://www.alz.org/brain/01.asp

Histopathological FeaturesHistopathological Features

Plaques: depositPlaques: depositof proteinof proteinfragments calledfragments calledamyloidamyloid ββ--peptidespeptides

Tangles: twistTangles: twiststrands of anotherstrands of anotherprotein, protein, tautau

Decrease in Decrease in AChAChsecretionsecretion

Neuron lossNeuron loss www.ahaf.org/.../Brain_Neurons_AD_Normal.htm

Cholinergic NeuronsCholinergic Neurons

Known to be destroyedKnown to be destroyedin basal forebrainin basal forebrain Reduced cholinergicReduced cholinergic

transmissiontransmission Linked to cognitive andLinked to cognitive and

non-cognitive symptoms innon-cognitive symptoms inpatientspatients

Due to decrease inDue to decrease inactivity of activity of cholinecholineacetyltransferaseacetyltransferase Synthesizes acetylcholineSynthesizes acetylcholine

Neuroscience, Neuroscience, PurvesPurves

Cholinesterase InhibitorsCholinesterase Inhibitors

AChEAChE and and BChEBChE involved in degradation of involved in degradation ofacetylcholineacetylcholine

Inhibition allows acetylcholine to be released intoInhibition allows acetylcholine to be released intosynaptic cleft and remain theresynaptic cleft and remain there Enhance cholinergic transmission and balanceEnhance cholinergic transmission and balance

cholinergic deficitcholinergic deficit Currently available drugs:Currently available drugs:

GalantamineGalantamine, , DonepezilDonepezil, , CognexCognex: selective inhibitors: selective inhibitorsof of AChEAChE

RivastigmineRivastigmine: Inhibits : Inhibits AChEAChE and and BChEBChEPositive effects on cognitive and functionalPositive effects on cognitive and functional

symptoms as well as behavioral abnormalitiessymptoms as well as behavioral abnormalities

Glutamate-MediatedGlutamate-MediatedNeurotoxicityNeurotoxicity

Excessive activation of NMDAExcessive activation of NMDAreceptors may play role in neuronalreceptors may play role in neuronaldeathdeath

NMDA antagonists for therapyNMDA antagonists for therapy MemantineMemantine: non-competitive antagonist: non-competitive antagonist

with moderate affinitywith moderate affinity No physiological effectsNo physiological effects Works at therapeutic concentrationsWorks at therapeutic concentrations Also inhibits Also inhibits tautau aggregation aggregation

Studies show it is well tolerated, usedStudies show it is well tolerated, usedfor moderate to severe Alzheimerfor moderate to severe Alzheimer’’s,s,and has beneficial effect on cognitiveand has beneficial effect on cognitivefunctionfunction

Combinatorial studiesCombinatorial studies

Excessive activation

Neurodegeneration

Increase in intracellular Ca2+

Neuroscience, Neuroscience, PurvesPurves

APP and Possible MutationsAPP and Possible Mutations Integral membrane proteinIntegral membrane protein

Signal sequenceSignal sequence Large Large extramembranousextramembranous region region

Mutations in APPMutations in APPgenegene Increased cleavageIncreased cleavage

by by ββ-secretase-secretase Leads to rise inLeads to rise in

overall Aoverall Aββgenerationgeneration

Mutations in genesMutations in genesfor presenilin-1 andfor presenilin-1 and-2-2 Alter APPAlter APP

metabolism throughmetabolism througheffect on effect on γγ--secretasesecretase

Single Single transmembranetransmembrane domain domain Small Small cytosoliccytosolic C-terminal tail C-terminal tail Found on chromosome 21Found on chromosome 21

SelkoeSelkoe, D. J. et. al. , D. J. et. al. ScienceScience, , 20022002, 297, 353-356, 297, 353-356

AmyloidAmyloid ββ-peptide-peptide

Normal product of APPNormal product of APPmetabolism throughout lifemetabolism throughout life Measured in CSF and plasmaMeasured in CSF and plasma

Allowed scientists to establishAllowed scientists to establishbiochemical abnormalities causedbiochemical abnormalities causedby APP mutationsby APP mutations

Primary component of brainPrimary component of brainplaquesplaques

This accumulation is primaryThis accumulation is primaryevent in AD event in AD pathogenisispathogenisis

SelkoeSelkoe, D. J. et. al. , D. J. et. al. ScienceScience, , 20022002, 297, 353-356, 297, 353-356

http://www.emdbiosciences.com/docs/docs/LIT/alzheimers_E.pdf

Strategies to Combat AStrategies to Combat Aββ

Inhibit Inhibit ββ- or - or γγ-secretase-secretase Prevent Prevent oligomerizationoligomerization of A of Aββ or enhance or enhance

its clearance from the cerebral cortexits clearance from the cerebral cortex Anti-inflammatory strategyAnti-inflammatory strategy Cholesterol lowering drugsCholesterol lowering drugs CuCu2+2+/Zn/Zn2+2+ chelatorschelators

ββ-secretase-secretase Major focus of drug discoveryMajor focus of drug discovery BACE1: primary BACE1: primary ββ-secretase -secretase in vivoin vivo

BACE1 knockouts had only very small amounts of ABACE1 knockouts had only very small amounts of Aββ Decreased plaque formationDecreased plaque formation

ID of small molecule inhibitors of ID of small molecule inhibitors of ββ-secretase-secretasemay be difficultmay be difficult

γγ-secretase-secretase Activity is prevented in PS1 deficient mouseActivity is prevented in PS1 deficient mouse

embryosembryos PS1 is linked to PS1 is linked to intramembraneintramembrane cleavage of APP cleavage of APP PS1 provides active core of PS1 provides active core of secretasesecretase activity activity

γγ-secretase-secretase inhibiting compound (LY450139) inhibiting compound (LY450139) Complete inhibition?Complete inhibition?

αα--secretasesecretase

Non-Non-amyloidogenicamyloidogenic Can be stimulated by Can be stimulated by muscarinicmuscarinic acetylcholine- acetylcholine-

receptor agonistsreceptor agonists Shown to reduce AShown to reduce Aββ formation in culture formation in culture

M1 agonist useful for symptomatic treatmentM1 agonist useful for symptomatic treatment AF267BAF267B

Reduced both Reduced both amyloidamyloid plaques and plaques and tautau tangles tangles Improved cognitive deficit in transgenic miceImproved cognitive deficit in transgenic mice

Inhibition of AggregationInhibition of Aggregation

AlzhemedAlzhemed Binds to ABinds to Aββ peptides to inhibit formation peptides to inhibit formation February 2007: completed Phase III clinicalFebruary 2007: completed Phase III clinical

trials with 5 recommendations from DSMBtrials with 5 recommendations from DSMB

CuCu2+2+/Zn/Zn2+2+

ClioquinolClioquinol: antibiotic and Cu/Zn : antibiotic and Cu/Zn chelatorchelator Significant decrease in ASignificant decrease in Aββ deposition after 9 deposition after 9

weeksweeks Phase III cancelledPhase III cancelled

AAββ Immunotherapy Immunotherapy

AAββ antibodies reduced: antibodies reduced: AmyloidAmyloid deposition deposition NeuriticNeuritic dystrophy dystrophy Synaptic degenerationSynaptic degeneration

ProblemsProblems Mechanism not fully understoodMechanism not fully understood One trial stopped due to asepticOne trial stopped due to aseptic

meningoencephalitismeningoencephalitis in 6% of patients in 6% of patients Currently:Currently:

Monoclonal AbMonoclonal Ab DNA vaccinesDNA vaccines

Early Early tautau accumulation accumulation Learning deficitsLearning deficits Memory deficitsMemory deficits

TauTau Microtubule associated proteinMicrotubule associated protein HyperphosphorylatedHyperphosphorylated form aggregates to form aggregates to

form form neurofibrillaryneurofibrillary lesions of tangles lesions of tangles Early event in ADEarly event in AD Decreases Decreases tautau’’ss ability to bind to and stabilize ability to bind to and stabilize

microtubulesmicrotubules Detachment from microtubuleDetachment from microtubule Breakdown of microtubule networkBreakdown of microtubule network Disturbance of axonal transportDisturbance of axonal transport NeurodegenerationNeurodegeneration

http://www.emdbiosciences.com/docs/docs/LIT/alzheimers_E.pdf

http://www.alz.org/brain/01.asp

Inhibition of Inhibition of TauTauHyperphosphorylationHyperphosphorylation

30 30 phosphorylationphosphorylation sites sites……many many manymany kinaseskinases Which sites are important?Which sites are important?

Cell culture vs. Cell culture vs. in vivoin vivo GSK3: inhibition for 30 days reducedGSK3: inhibition for 30 days reduced

hyperphosphorylationhyperphosphorylation at several sites and decreased at several sites and decreasedtautau aggregation aggregation

KinaseKinase inhibitor: prevented inhibitor: prevented tautau hyperphosphorylationhyperphosphorylationin cell and brain slice culture modelsin cell and brain slice culture models Delay in onset of motor deficitsDelay in onset of motor deficits

Imbalance of Imbalance of kinaseskinases and and phosphatasesphosphatases

ConclusionsConclusions

There are many processes dealing with ADThere are many processes dealing with AD No single one is fully understoodNo single one is fully understood

AmyloidAmyloid ββ-peptide plaques and -peptide plaques and tautau aggregation aggregationseem to be main contributors to AD symptomsseem to be main contributors to AD symptoms Also offer most opportunities for treatmentAlso offer most opportunities for treatment

AChACh and glutamate may play different roles in and glutamate may play different roles inAD patientsAD patients

While there is not a cure, there are manyWhile there is not a cure, there are manyavenues of attack to cure ADavenues of attack to cure AD

ReferencesReferences

BartusBartus, R. T. et. al. , R. T. et. al. ScienceScience, , 1982 1982, 217, 408-414., 217, 408-414. Hardy, J. et. al. Hardy, J. et. al. ScienceScience, , 20022002, 297, 353-356., 297, 353-356. HenekaHeneka, M. et. al. , M. et. al. Drugs, Drugs, 20062006, 66 (16), 2075-2093., 66 (16), 2075-2093. MuckeMucke, L. et. al. , L. et. al. ScienceScience, , 20062006, 314, 781-784., 314, 781-784. NeuroscienceNeuroscience, , PurvesPurves, D. et. al. 3, D. et. al. 3rdrd Ed. Ed. SinauerSinauer

Associates, Inc. Associates, Inc. Sunderland , MA. Sunderland , MA. 20042004.. ScarpiniScarpini, E. et. al. , E. et. al. Lancet. Lancet. NeurolNeurol.., , 20032003, 2, 539-547., 2, 539-547. SelkoeSelkoe, D. J. et. al. , D. J. et. al. ScienceScience, , 20022002, 297, 353-356., 297, 353-356. SpillantiniSpillantini, M. G. et. al. , M. G. et. al. ScienceScience, , 20062006, 314, 777-780., 314, 777-780. WiltfangWiltfang, J. et. al. , J. et. al. Brain, Brain, 20062006, 129, 2840-2855., 129, 2840-2855. www.neurochem.comwww.neurochem.com, , NeurochemNeurochem, 4/18/07., 4/18/07. www.alz.orgwww.alz.org, Alzheimer, Alzheimer’’s Association, 4/14/07.s Association, 4/14/07.