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《Bartzokis_Age-related-myelin-breakdown-a-developmental-model-of-cognitive-decline-and-Alzheimer’s-disease_2004》由會員上傳分享，免費在線閱讀，更多相關(guān)內(nèi)容在學術(shù)論文-天天文庫。
1、NeurobiologyofAging25(2004)518OpenpeercommentaryAge-relatedmyelinbreakdown:adevelopmentalmodelofcognitivedeclineandAlzheimersdiseaseGeorgeBartzokisa,b,c,?aDepartmentofNeurology,UCLAAlzheimer’sDiseaseCenter,710WestwoodPlaza,Room2-238,LosAngeles,CA90095,
2、USAbLaboratoryofNeuroimaging,DepartmentofNeurology,DivisionofBrainMapping,UCLA,LosAngeles,CA90095,USAcGreaterLosAngelesVAHealthcareSystem,WestLosAngeles,CA90073,USAReceived24January2003;accepted21March2003AbstractAhypotheticalmodelofAlzheimersdisease(A
3、D)asauniquelyhumanbraindisorderrootedinitsexceptionalprocessofmyelinationispresented.CorticalregionswiththemostprotracteddevelopmentaremostvulnerabletoADpathology,andthisprotracteddevelopmentisdrivenbyoligodendrocytes,whichcontinuetodifferentiateintomy
4、elinproducingcellslateintothe?fthdecadeoflife.Theuniquemetabolicdemandsofproducingandmaintainingtheirvastmyelinsheathsandsynthesizingthebrainscholesterolsupplymakeoligodendrocytesespeciallysusceptibletoavarietyofinsults.Theirvulnerabilityincreaseswithi
5、ncreasingageatdifferentiationaslater-differentiatingcellsmyelinateincreasingnumbersofaxonalsegments.Thesevulnerablelate-differentiatingcellsdrivetheprotractedprocessofintracorticalmyelinationandbyincreasinglocalcholesterolandironlevels,progressivelyinc
6、reasethetoxicityoftheintracorticalenvironmentformingthebasisfortheageriskfactorforAD.Atolderages,theroughlybilaterallysymmetricalcontinuumofoligodendrocytevulnerabilitymanifestsasaprogressivepatternofmyelinbreakdownthatrecapitulatesthedevelopmentalproc
7、essofmyelinationinreverse.Theensuinghomeostaticresponsestomyelinbreakdownfurtherincreaseintracorticaltoxicityandresultsintherelentlessprogressionandnon-randomanatomicaldistributionofADlesionsthateventuallycauseneuronaldysfunctionanddegeneration.Thispro
8、cesscausesaslowlyprogressivedisruptionofneuralimpulsetransmissionthatdegradesthetemporalsynchronyofwidelydistributedneuralnetworksunderlyingnormalbrainfunction.Theresultingnetworkdisconnections?rstimpactfunctionsthataremostdependentonla
