大脑衰老神经科学

OnderAlbayram,PhDMedicalUniversityofSouthCarolinaDepartmentofPathologyandLaboratoryMedicinealbayram@NSCS730C

BrainAging:

Age-dependentNeurodegenerativeDisordersOutlineTheoriesofAgingBrainAging

-NormalBrainAging-PathologicalBrainAgingDementia-Alzheimer’sDisease-VascularDementia-LewyBodyDementia-FrontotemporalDementiaResearchStudywithNormalAging&Dementia-Thecannabisparadox:whenagemattersTheoriesofAgingGeneticAgingisrelatedtoageneticprogramactivatedinpost-reproductivelifewhenanindividual'sevolutionarymissionisaccomplished.OxidativestressAgingisrelatedtotheaccumulationofoxidativedamagetoDNA,proteins,andlipidsinterfereswithnormalfunctionandproducesadecreaseinstressresponses.MitochondrialdysfunctionAgingisrelatedtoacommondeletioninmitochondrialDNAwithagecompromise'sfunctionandalterscellmetabolicprocessesandadaptabilitytoenvironmentalchange.TheoriesofAgingHormonalChangesAgingisrelatedtodeclineandlossofcircadianrhythminsecretionofsomehormonesproducesafunctionalhormonedeficiencystate.TelomereShorteningAgingisrelatedtoadeclineintheabilityofcellstoreplicate.DefectiveHostDefensesAgingisrelatedtofailureoftheimmunesystemtorespondtoinfectiousagentsandtheoveractivityofnaturalimmunitycreatevulnerabilitytoinflammation.BrainAgingNormalBrainAgingBrainandspinalcordlosenerveandweight.Nervecellstransmitmessagesmoreslowly.Wasteproductscollectinbraintissueasnervecellsbreakdowncreatingabnormalstructures.Reducedorevenlostreflexesandsensation.Slowingofthoughtandmemory..BrainAgingNormalBrainAging(Structural)StructureRegionalfunctionBasalgangliaBecomesbrightinappearanceduetoironaccumulation.SubarachnoidspaceIncreaseinsizeduetobrainshrinkage.HippocampusReductioninsizeduetocelllossinthestructure.VentriclesIncreaseinsizeduebrainshrinkage.WhiteMatterReductioninsizeduetoneuronalatrophyinthedeepbrain.Age-RelatedMemoryChanges-1Informationisstoredin3partsofmemory:-Short-TermMemoryie:thenameofapersonmetminutesago-RecentMemoryie:whatwasforbreakfast-RemoteMemoryie:memoriesofchildhoodAge-RelatedMemoryChanges-2Agingmaychangethewaythebrainstoresinformationmakingithardertoremember.Short-termandremotememoriesarenotusuallyaffected,butrecentmemorycanbeaffected.MildCognitiveImpairment(MCI)MCIisthestagebetweentheexpectedcognitivedeclineofnormalagingandthemoreseriousdeclineofdementia.MCIisdefinedbydeficitsinmemorythatdonotsignificantlyimpactdailyfunctioning.DementiaDementiaisatermusedtodescribeagroupofsymptomsaffectingmemory,thinkingandsocialabilitiesseverelyenoughtointerferewithyourdailylife.Alzheimer’s60%-80%Vascular20%-40%Lewy

Bodies10%-25%Frontotemporal~10%DementiaAn‘umbrella’termusedtodescribearangeofsymptomsassociatedwithcognitiveimpairmentAlzheimer’sDiseaseAlzheimer'sdiseaseisthemostcommoncauseofaprogressivedementiathatcausesthebraintoshrink(atrophy)andbraincellstodie.Age(notapartofnormalaging).Certaincombinationofgenesforproteins.Longstandinghighbloodpressure.Historyofheadtrauma.Gender.Alzheimer’sDiseaseAlzheimer'sdiseaseisbelievedtooccurwhenabnormalamountsofAβ,accumulatingextracellularlyasamyloidplaquesandtauproteins,orintracellularlyasneurofibrillarytangles,forminthebrain,affectingneuronalfunctioningandconnectivity,resultinginaprogressivelossofbrainfunction.Alzheimer’sDiseaseTwoTypes:-EarlyOnset:Symptomsbeforeage60andmuchlesscommon.-LateOnset:Symptomsafterage60andmuchmorecommon.Diagnosis:TheonlywaytoknowforcertainthatsomeonehasAlzheimer’sistoexamineasampleoftheirbraintissueafterdeath.Thislossresultsingrossatrophyoftheaffectedregions,includingdegenerationinthetemporallobeandparietallobe,andpartsofthefrontalcortexandcingulategyrus.Prevention:Therearenodisease-modifyingtreatmentsavailabletocureAlzheimer'sdiseaseandbecauseofthis,ADresearchhasfocusedoninterventionstopreventtheonsetandprogression.VascularDementiaMulti-embolicinfarctsandcerebralhypoperfusionaremajorfactorsinvasculardementia(VaD).DiffusewhitematterlesionsisacriticalcomponentofVaDandcorrelatewithcognitiveimpairment.Thefactthat~50%ofhumandementiapatientshavemixedvascularandAlzheimer’spathologies.TautanglesareaneuropathologicalhallmarkofAD,butpureVaDhumanbrainsdonothaveobvioustautanglepathology.NotanglepathologyinhumanVaDbrains

Corpuscallosum(white-matter)ControlVaDControlVaDControlVaDDAPI+

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Iba1VerifiedpureVaDhumanbrainsobtainedfromtheNetherlandsBrainBankhadsignificantdemyelination,aswellasneuroinflammationScienceTranslationalMedicine

(2021)RobustcisP-taunotablyincingulatecortexoverlyingthecorpuscallosuminhumanVaDbrainscisP-tau(Near-infraredIFimaging)

ControlVaDCingulatecortexCorpuscallosumControl-1VaD-1Control-3Control-2VaD-4VaD-3VaD-5VaD-6VaD-2DAPI

+cisP-tau(ConfocalIFimaging)

ScienceTranslationalMedicine

(2021)microcoilRelevanceofcisP-tauandPin1toVaDusingabilateralcommoncarotidarterystenosis(BCAS)mousemodelModelofChronicCerebralHypoperfusion:Bilateralplacementofmicrocoilsaroundthecommoncarotidarteriestoreduceparenchymalcerebralbloodflowby~50%.(0.18mmdiameter)ScienceTranslationalMedicine

(2021)microcoil02MDay3Day7Day14BCASCisP-tauIFintensity

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+cisP-tauShamDay3Day7Day14cisP-tauimmunoreactivityShamDay3Day7Day14BCASsurgeryinducedcisP-tauintheregionoverlayingthecorpuscallosummiceinatime-dependentmannerDay28ScienceTranslationalMedicine

(2021)BCASmiceshowsclearworkingmemorydeficitsat28days

ShamBCAS2MPercentofcorrect(%)DiscriminationratioT-MazeDay28Day28Novelobjectrecog.Day28BCASSham

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MBPDay28BCASsurgeryinducecisP-tau,whichaccompaniedwithneuroinflammationanddemyelinationat28daysScienceTranslationalMedicine

(2021)LewyBodyDementia(LBD)LBDisadiseaseassociatedwithabnormaldepositsofaproteincalledalpha-synucleininthebrain.Thesedeposits,calledLewybodies,affectchemicalsinthebrainwhosechanges,inturn,canleadtoproblemswiththinking,movement,behavior,andmood.LewyBodyDementia(LBD)AccumulationofLewybodiesisassociatedwithalossofcertainneuronsinthebrainthatproducetwoimportantneurotransmitters(AcetylcholineandDopamine).HavingafamilymemberwithLBDalsomayincreaseaperson'srisk,thoughLBDisnotconsideredageneticdisease.LBDreferstoeitheroftworelateddiagnoses—dementiawithLewybodies(DLB)andParkinson'sdiseasedementia.FrontotemporalDementia(FTD)Frontotemporaldementiaisanumbrellatermforagroupofbraindisordersthatprimarilyaffectthefrontalandtemporallobesofthebrain.Theseareasofthebrainaregenerallyassociatedwithpersonality,behaviorandlanguage.Infrontotemporaldementia,portionsoftheselobesshrink(atrophy).FrontotemporalDementia(FTD)ThecauseofFTDisunknown.FTDhavetinystructures,calledPickbodies,intheirbraincells.Pickbodiescontainanabnormalamountortypeofprotein.Thesedisordersareamongthemostcommondementiasthatstrikeatyoungerages.Symptomstypicallystartbetweentheagesof40and65,butFTDcanstrikeyoungadultsandthosewhoareolder.FTDaffectsmenandwomenequally.TheendocannabinoidsysteminbrainagingTheScienceBehindCannabis:TheEndocannabinoidSystemMatsuda,Letal.,1990(Nature)DevaneW,andMechoulamR,etal.,1992(Science)©NationalGeographicPlant-derivedcannabinoidTetrahydrocannabinol(THC)EndogenouscannabinoidsArachidonicacid(AG)Anandamide(AEA)Thereducedethanolpreferenceinyoung,butnotoldCB1receptorknockoutmice

(OLD)9-monthsoldEthanolPreferenceEtOHIntake(g/kg/day)

(YOUNG)2-monthsoldEthanolPreferenceEtOHIntake(g/kg/day)GeorgeKunos,Ph.D.NIHonAlcoholAbuseandAlcoholismPNAS(2003)FoodintakeisreducedbyCB1receptorantagonistinyoung,butnotinoldmice0123h8060402000123h806040200

FoodIntake(g/kgmouse)FoodIntake(g/kgmouse)

(OLD)9-monthsold

(YOUNG)2-monthsoldPNAS(2003)Theendocannabinoidsystemactivityundergoesanage-relateddeclineinmousehippocampusQuantitativeLC-MSanalysisofAGAGlevelinhippocampus(nmol/g)ExpressionofAGbiosynthesisenzymeDAGLα-IRsignalaverageintensity2-monthsold12-monthsold%ofmRNAexpression(ΔΔCT)ExpressionofCB1rmRNA2-monthsold12-monthsold2-monthsold12-monthsoldPNAS(2011)EuropeanJournalofPhysiology(2016)MicelackingCB1receptorsshowacceleratedagingasevidencedbyearlyonsetofbrainagingsymptomsPNAS(2011)EuropeanJournalofPhysiology(2016)2-monthsold12-monthsold©PNASandUniversityofBonnPressWhatwouldbethemechanismsofage-relateddeclineofcannabinoidsignaling?Whetherthereisapossiblesolutiontorestorethephysiologicallevelofcannabinoidsignalinginoldanimals?ChronicTHCtreatmentimprovesmemoryinoldmiceNOR0

Vehicle14284256NORNORNORNORNovelobjectrecognition(NOR)testDaysNatureMedicine(2017)%ofexploratorypreference114284256Days12-monthsoldmiceVehicleTHCEndofthedrugadministrationChronicTHCtreatmentimprovesmemoryinoldmice0