10rev Is Alzheimer’s Disease a Disorder of

AD REVIEW

JournalofAlzheimer’sDisease20(2010)S281–S292DOI10.3233/JAD-2010-100495IOSPress

S281

Review

IsAlzheimer’sDiseaseaDisorderofMitochondria-AssociatedMembranes?

EricA.Schona,b, andEstelaArea-Gomeza

a

DepartmentofNeurology,ColumbiaUniversityMedicalCenter,NewYork,NY,USAb

DepartmentofGeneticsandDevelopment,ColumbiaUniversityMedicalCenter,NewYork,NY,USA

Accepted5April2010

Abstract.Thesubcellularlocalizationofpresenilin-1(PS1)andpresenilin-2(PS2),twoproteinsthat,whenmutated,causefamilialAlzheimer’sdisease(AD),iscontroversial.Wehavediscoveredthatmitochondria-associatedmembranes(MAM)–aspecializedsubcompartmentoftheendoplasmicreticulum(ER)involvedinlipidmetabolismandcalciumhomeostasisthatphysicallyconnectsERtomitochondria–isthepredominantsubcellularlocationforPS1andPS2,andforγ-secretaseactivity.WehypothesizethatpresenilinsplayaroleinmaintainingMAMfunction,andthatnotonlyalteredamyloid-βlevelsandhyperphosphorylatedtau,butalsomanyotherfeaturesofAD(e.g.,alteredphospholipidandcholesterolmetabolism,aberrantcalciumhomeostasis,andabnormalmitochondrialdynamics)resultfromcompromisedMAMfunction.Thelocalizationofpresenilinsandγ-secretaseinMAMmayhelpreconciledisparateideasregardingthepathogenesisofAD,underaunifyinghypothesisthatcouldexplainmanyfeaturesofbothsporadicandfamilialAD,therebytakingADresearchinanewandfruitfuldirection.

Keywords:Alzheimer’sdisease,calcium,cholesterol,endoplasmicreticulum(ER),mitochondria,mitochondria-associatedmem-branes(MAM),phospholipids

ALZHEIMER’SDISEASE

Alzheimer’sdisease(AD),themostcommonlateonsetneurodegenerativedementingdisorder,ischarac-terizedbyprogressiveneuronalloss,especiallyinthehippocampusandcortex[1].Thetwomainhistopatho-logicalhallmarksofADaretheaccumulationofextra-cellularneuriticplaques,containingamyloid-β(Aβ),andofneuro brillarytangles,consistingmainlyofhy-perphosphorylatedformsofthemicrotubule-associatedproteintau[1].MostADpatientsaresporadic(SAD),butthreegeneshavebeenassociatedwiththefamil-ialform(FAD):amyloid-βproteinprecursor(AβPP),presenilin-1(PS1),andpresenilin-2(PS2).Clinically,FADissimilartoSADbuthasearlieronset.

to:EricA.Schon,PhD,CollegeofPhysicians&

Surgeons,RoomP&S4-449,ColumbiaUniversityMedicalCenter,630West168thStreet,NewYork,NY10032,USA.Tel.:+12123051665;Fax:+12123053986;E-mail:eas3@columbia.edu.

CorrespondencePresenilinsarecomponentsoftheγ-secretasecom-plex(alsocontainingAPH1,nicastrin,andPEN2)that,togetherwithβ-secretase,processesAβPPtoproduceAβ[1].Inthemainstreamview,bothSADandFADarisewhenAβPPisprocessedtoAβ,whichaccu-mulatesinextracellularplaques.Aβistoxictocellsandtheresultingstresspromotestauhyperphosphory-lation,leadingtothetangles.Theoverallprocesshasbeencalledthe“amyloidcascade”hypothesis[2,3].Thishypothesisreconciles ndingsfromdifferentap-proachestothediseaseandhasservedasthebasisformanykeyexperimentsinvivoandinvitro.However,certainquestionsthatarecentraltounderstandingthepathogenesisofADandtheprocessingofAβremainunsolved.

The rstquestionconcernsfeaturesofADthatarenotobviouslylinkedtoplaqueortangleformation.Whileplaquesandtanglesarehallmarksofthedis-ease,otherapparentlyunrelatedlaboratoryabnormali-

ISSN1387-2877/10/$27.50 2010–IOSPressandtheauthors.Allrightsreserved

AD REVIEW

S282E.A.SchonandE.Area-Gomez/MAMDysfunctioninADPathogenesis

tiesareroutinelydetectedinpatients,includingelevat-edcholesterol[4],alteredfattyacid[5,6],glucose[7,8],andphospholipid[9]metabolism,aberrantcalciumhomeostasis[10],andmitochondrialdysfunction[11].ThesefeaturesofADhavereceivedfarlessattentionbecauseofthelackofdirectlinkstotheamyloidcas-cade,andhaveengenderednumerouscompetinghy-pothesestoexplainthepathogenesisofAD.Thesein-cludetauhyperphosphorylation[12],alteredlipid[13],cholesterol[14],andglucosemetabolism[15,16],aber-rantcalciumhomeostasis[17],glutamateexcitotoxic-ity[18],in ammation[18,19],ERstressandtheun-foldedproteinresponse(UPR)[20–23],andmitochon-drialdysfunctionandoxidativestress[24].Itremainstobedeterminedtowhatdegreethesephenomenaarecausallyinterlinked,andwhethertheymaybedirectoutcomesofdefectsinAβPPprocessing.

Thesecondissueiscommonlyreferredtoasthe“spatialparadox”[25]:whereasPS1isbelievedtobelocatedmainlyintheER[26]andGolgi[26,27]asacomponentofanintracellularγ-secretase[28],pro-cessingofAβPPtoreleaseextracellularAβisbelievedtooccuratorneartheplasmamembrane(PM)[29].Thus,thereisanapparentphysicaldisconnectbetweentheintracellularlocationofpresenilinsandγ-secretaseactivityontheonehandandthepresumedsiteofAβsynthesisontheother.

Onepotentialsolutiontothespatialparadoxwouldbetoreviseourcurrentopiniononthesubcellulardis-tributionsofpresenilins.Indeed,althoughmanybe-lievethatpresenilinsarelocatedintheERand/orGol-gi,intruth,thesubcellularlocalizationofPS1andPS2hasbeenthesubjectofcontroversy,withlocalizationsreportedinothercompartments,includingthenuclearenvelope[30],endosomes[31],lysosomes[32],mito-chondria[33],andtheplasmamembrane[28],whereitisespeciallyenrichedatintercellularcontactsknownasadherensjunctions[34].

OurunderstandingofthepathogenesisofAD,andbyextension,oureffortstodeveloptherapiesforthisdevastatingdisorder,ishighlydependentonapreciselocalizationofthiskeyproteolyticeventandpotentialtherapeutictarget.

MITOCHONDRIA-ASSOCIATEDMEMBRANES

Mitochondria-associatedERmembranes(MAM)isaspecializedsubcompartmentoftheERthatconnectsthisorganelletomitochondria,bothbiochemicallyand

physically[35–38].Itplaysacriticalroleincalciumhomeostasis,aswellasinvarioushousekeepingfunc-tions,suchasphospholipid,glucose,sphingolipid,gan-glioside,cholesterol,andfattyacidmetabolism[38],aswellasincalciumhomeostasisandsignaling[38]andinapoptosis[39].Thisphysicalconnectionhasbeenproposedtobemediatedbyphosphofurinacidicclustersortingprotein2(PACS2)[39]andmitofusin2(MFN2)[40].

MAMisdistinctfrom“bulk”ERinitscompositionandbehavior.Forexample,MAMisenr …… 此处隐藏：46662字，全部文档内容请下载后查看。喜欢就下载吧 ……