Me Me Tab sis Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration Part 3

Microglia-Derived Exosomes: Microglial hlwb yog cov macrophages ntawm lub hlwb thiab qaum qaum. Lawv suav txog kwv yees li 10% ntawm glia.

Microglia yog ib hom cell uas tsis yog-neuronal nyob rau hauv lub hlwb thiab yog cov hlwb ntau tshaj plaws nyob rau hauv lub paj hlwb. Yav dhau los, microglia tau xav tias yog cov hlwb txhawb nqa neuron uas tsuas yog muab cov pa oxygen thiab cov as-ham.

Txawm li cas los xij, kev tshawb fawb tsis ntev los no tau pom tias microglia ua lub luag haujlwm tseem ceeb hauv tib neeg kev noj qab haus huv thiab kev paub txog kev ua haujlwm. Cov kev tshawb fawb tau pom tias microglia ua lub luag haujlwm tseem ceeb hauv kev kawm thiab kev nco.

Microglia feem ntau txhawb kev loj hlob thiab kev loj hlob ntawm cov neurons los ntawm kev tso cov khoom hu ua neuronal kev loj hlob zoo. Qhov kev loj hlob zoo li no tsis tsuas yog pab cov neurons txuas thiab xa cov ntaub ntawv tab sis kuj tseem txhawb kev tsim cov neurons tshiab. Cov teebmeem no tseem ceeb heev rau kev tswj kev kawm noj qab haus huv thiab kev nco.

Ntawm qhov tod tes, microglia tseem tuaj yeem tshem tawm ntau cov neurons thiab synapses hauv lub hlwb thiab txhawb kev txhim kho kev noj qab haus huv ntawm lub paj hlwb. Cov txheej txheem tshem tawm no tuaj yeem pab txo cov teeb meem cuam tshuam hauv lub hlwb thiab txhim kho kev paub txog kev ua haujlwm.

Tsis tas li ntawd, microglia tuaj yeem tiv thaiv cov neurons los ntawm kev puas tsuaj oxidative los ntawm kev txhawb nqa kev tuaj txog ntawm cov pa oxygen thiab cov as-ham hauv lub hlwb. Cov hlwb no tseem ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kev paub txog kev puas hlwb thiab neurodegeneration.

Hauv ntej, qhov tseem ceeb ntawm microglia tsis tuaj yeem kwv yees. Lawv tuaj yeem tiv thaiv neurons thiab pab txoj kev kawm thiab kev nco. Peb yuav tsum tiv thaiv thiab txhim kho tus naj npawb thiab kev ua haujlwm ntawm microglia kom ntau li ntau tau los xyuas kom muaj kev noj qab haus huv thiab tseem ceeb ntawm peb lub hlwb. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim tias nws tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob, uas tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov khoom noj txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub txoj hauv kev los txhim kho lub hlwb

Txawm hais tias lawv cov lej muaj qhov sib piv tsawg, lawv muaj lub luag haujlwm tseem ceeb ntawm kev tswj hwm homeostasis los ntawm kev saib xyuas cov ntaub so ntswg thiab kev puas tsuaj hauv CNS.

Nyob rau hauv homeostatic tej yam kev mob, microglia hlwb tau khaws cia nyob rau hauv ib tug quiescent lub xeev, tab sis lawv yog tas li scanning lawv ib puag ncig. Thaum ua haujlwm, lawv tawm dag zog lawv cov haujlwm phagocytic thiab tuaj yeem tso tawm cov kab mob inflammatory xws li cytokines, thiab chemokines.

Microglia tuaj yeem tau txais ob hom phenotypes, M1 (mob mob) thiab M2 subtypes (pro-regenerative type), nyob ntawm qhov stimuli thiab tuaj yeem hloov ntawm ob qhov kev tawm tsam phenotypes [140], piv txwv li lawv cov plasticity zoo kawg li.

Zoo ib yam li cov neurons thiab lwm cov hlwb, microglia tso tawm exosomes sib txuas lus nrog cov hlwb nyob sib ze thiab cov hlwb nyob deb. Lub bioactive cargo ntawm microglial exosomes nyob ntawm qhov phenotype ntawm qhov tso tawm microglia, xws li pro-inflammatory lossis pro-regenerative. Microglial exosomes muaj tag nrho cov enzymes tseem ceeb rau anaerobic glycolysis thiab lactate ntau lawm.

Yog li, itis tau hais tias lactate ntim rau hauv exosomes tuaj yeem ua haujlwm ntxiv rau lub zog rau cov neurons thaum lub sijhawm ua haujlwm synaptic [141]. Microglial exosomes tswj synaptictransmission los ntawm kev txhawb nqa ceramide thiab sphingolipid ntau lawm hauv neurons.

Enhancedsphingolipid metabolism zoo cuam tshuam rau excitatory neurotransmission nthuav tawm ib txoj kev tshiab uas microglia cuam tshuam kev ua haujlwm synaptic [142]. Tau ntsib nrog kev kis kab mob thiab / orinjury, microglial hlwb sai sai ua rau cov lus teb nyuaj thiab tau txais M1 phenotype.

Microglia tam sim no nrog cov tshuaj tiv thaiv kab mob phenotype (M1 phenotype) tso tawm exosomes uas pab nrog kev txhim kho neuroinflammation. Cov ntaub ntawv pov thawj formicroglial exosome kev koom tes hauv neuroinflamation los ntawm kev tshawb fawb nrog lipopolysaccharide (LPS).

Kev nthuav tawm ntawm microglia rau LPS, ib qho tseem ceeb ntawm cov kab mob Gram-negative, ua rau kom tso tawm ntawm exosomes enriched nrog IL-1, pro-inflammatorycytokine, thiab microRNAs xws li miR-155 thiab miR{{4} }. MicroRNA 155 yog ib qho tseem ceeb tswj microRNA hauv lub cev tiv thaiv kab mob thiab nws cov qib nce ntxiv tau kuaj pom hauv cov kab mob inflammatory [143].

Hauv lwm txoj kev tshawb fawb, microglial hlwb tau kho nrog LPS uas nce kev qhia ntawm N-myc downregulated gene 2 (NDRG2) protein ntau ntau. NDRG2 protein ntau ntxiv nyob rau hauv lem stimulated microglia kom tso tawm miR-375 enriched exosomes.Internalization ntawm miR-375 enriched exosomes txo lub cell viability ntawm N2A neurons qhia txog cov xwm txheej neurotoxic ntawm cov exosomes [144].

Nws zoo nkaus li tias raug LPS altersmicroRNAs thiab cov proteins ntim hauv exosomes. Cov ntaub ntawv pov thawj tau los ntawm kev tshawb fawb txog BV2 hlwb. Cov BV2 hlwb ntawm C57 Cov nas dub yog cov hlwb tsis txawj tuag.Thaum BV2 hlwb raug rau LPS, lawv tso tawm exosomes nplua nuj nyob rau hauv pro-inflammatory cytokines IL-6 thiab TNF thiab cov proteins cuam tshuam txog kev txhais lus thiab kev sau ntawv.

Cov proteomicprofile ntawm exosomes soj ntsuam los ntawm huab hwm coj spectrometry txheeb xyuas 49 cov proteins tshwj xeeb uas muaj nyob rau hauv exosomes los ntawm LPS-kho BV2 hlwb piv rau tswj BV2 hlwb.

Nws yog ib qho tsim nyog sau cia qhov no tias exosomes los ntawm LPS-activated microglia muaj 58 proteins thaum exosomes los ntawm kev tswj BV2 hlwb muaj 37 proteins [145]. Cov kev sib tham yav dhau los qhia tau hais tias microglial exosomes yog qhov tseem ceeb hauv kev txhawb nqa neuroprotective thiab neuroinflammatoryfunctions ntawm microglial hauv CNS.

4. Lub luag haujlwm ntawm Exosomes hauv Cov Kab Mob Neurodegenerative

Ntau cov kab mob neurodegenerative cuam tshuam nrog kev sib txuam ntawm qhov txawv txav, misfolded proteins ua rau muaj kev loj hlob ntawm neural thiab glial dysfunction. Feem ntau, cov kab mob neurodegenerative pib nrog kev ua haujlwm tsis zoo hauv thaj tsam ntawm lub hlwb.

Thaum tso tawm rau hauv qhov chaw sab nraud, cov proteins uas tsis zoo raug xa mus rau cov hlwb noj qab haus huv thiab pib induceendogenous counterpart proteins kom misfold zoo li cov nyhuv domino [160].

Qhov txheej txheem "kab mob" no ua rau kev nthuav dav ntawm cov kab mob pathology thiab kis tus kab mob mus rau ntau qhov chaw ntawm lub hlwb. Intercellular kev sib txuas lus tseem ceeb hauv kev sib kis thiab kev loj hlob ntawm cov kab mob neurodegenerative. Exosomes tso tawm los ntawm tag nrho cov hlwb nyob rau hauv lub hlwb tau dhau los ua ib qho tseem ceeb hauv kev sib txuas lus neuro-glia.

Lub peev xwm ntawm exosomes thauj thiab xa cov khoom thauj bioactive xws li lipids, RNAs, thiab cov proteins los ntawm ib lub xovtooj mus rau lwm qhov ua rau lawv ua tus neeg sib tw txaus nyiam ua cov neeg sib kho ntawm neurodegeneration. Hauv qab no, peb tham txog qhov cuam tshuam ntawm exosomes hauv cov kab mob xaiv neurodegenerative.

Alzheimer's Disease: Alzheimer's disease yog hom kab mob neurodegenerative dementia uas tshwm sim los ntawm kev poob ntawm kev nco thiab kev txawj ntse.

Central mus rau lub pathology ntawm Alzheimer's kab mob yog tsim ntawm extracellular aggregates ntawm -amyloid (A) hu ua amyloid plaques ua ke nrog neurofibrillary tangles ntawm tau.The (A) peptides yog muab los ntawm sequential proteolytic ua ntawm amyloid precursorprotein (APP) los ntawm - thiab - zais cia.

Raws li APP yog ib qho intracellular protein, ib qho kev xav tau tsim tawm tias cov kab mob pathological ntawm cov kab mob neurodegenerative cuam tshuam rau lub cev ntawm cov misfolded protein los ntawm neuron mus rau neuron [161].

Txawm li cas los xij, cov txheej txheem rau kev sib kis ntawm cov misfolded proteins tseem yog cov lus nug tsis txaus ntseeg. Ib qho ntawm cov ntaub ntawv tshaj tawm ntxov uas tau pib ua kom pom lub teeb pom kev zoo ntawm yuav ua li cas A yog los rau hauv qhov chaw sab nraud los ntawm txoj kev tshawb fawb los ntawm Rajendran thiab Cov npoj yaig [162].

Thaum tshawb xyuas qhov chaw ntawm APP cleavage, lawv tau pom tias -secretase cleavageof APP tshwm sim nyob rau hauv ib qho ntawm cov endosomes thaum ntxov nrog kev lag luam tom ntej ntawm A peptideto multivesicular lub cev.

Ib feem me me ntawm A peptide cuam tshuam nrog exosome membrane tau zais rau hauv qhov chaw ntxiv. Exosomes muaj amyloid plaques hadexosomal marker proteins, flotillin-1, thiab Alix. Yog li, exosome membrane-associated A peptide tuaj yeem sawv cev rau cov txheej txheem tshiab uas ua rau muaj amyloid plaque tsim nyob rau hauv qhov chaw extracellular [162].

Txij li thaum qhov kev soj ntsuam thawj zaug no, tag nrho-ntev APP thiab ntau ntawm nws cov metabolites thiab ntau tus tswv cuab ntawm tsev neeg secretase ntawm proteases koom nrog hauv APPprocessing tau kuaj pom hauv exosomes [163].

Ib qho tuaj yeem muaj nyob rau hauv cov conformationalstates sib txawv uas muaj cov khoom sib txawv thiab cov khoom nruab nrab ntawm fibril tsim. Ntawm no, qis-molecular-yuag A thiab protofibrils tau pom tias yog tshwj xeeb tshaj yog neurotoxic thiab ua raws li cov noob rau protein aggregation [164,165]. Exosomes cais los ntawm postmortem hlwb ntawm cov neeg mob Alzheimer's kab mob tau pom tias muaj ntau theem ntawm A oligomers. Cov exosomes no tau nyob rau hauv thaum incubated nrog cultured neurons.

Qhov tseem ceeb tshaj plaws, lawv muaj peev xwm kis tau A oligomers rau lwm cov neurons, ua rau cytotoxicity [166]. Cov kev soj ntsuam thawj zaug tau lees paub los ntawm incubating exosomes uas muaj APP nrog cov kab lis kev cai ntawm ib txwm neurons hauv vitro [167] thiab hauv vivo [168].

Cov lus nug yog vim li cas A lossis A oligomers ntim rau hauv exosomes? Puas yog cov neurons hnov ​​​​cov tshuaj lom neeg ntawm A lossis A oligomers thiab yog li sim tshem tawm cov proteins uas muaj kuab lom los ntawm intracellularly presentA lossis A oligomers zoo ib yam li hloov cov receptors hauv reticulocytes [7,8]? Monoubiquitination yog xav tau rau kev txheeb xyuas hauv MVB / exosomes. Qhov ntawd tsa ib lo lus nug thib ob raws li kev sib koom ua ke A undergoes ubiquitination los txheeb rau hauv MVB / exosomes. Lub amyloidprecursor protein (APP) muaj tsib lysine residues (Lys-724, Lys-725, Lys-726, Lys-751, thiabLys-763) ntawm nws C- Terminal kawg [169].

Cov residues no tau hloov pauv ib tus zuj zus los yog sib xyaw ua ke los tshuaj xyuas cov txiaj ntsig ntawm kev ua APP los ua A peptide. Ubiquitination ntawm APP ntawm Lys-726 kho los ntawm F-box thiab leucine-nplua nuj rov qab protein2 (FBL2), acomponent ntawm E3 ubiquitin ligase, txo A tiam [170]. Ntawm qhov tod tes, APP ubiquitination ntawm Lys-763 sequestered APP nyob rau hauv lub Golgi complex thiab tiv thaiv APPmaturation [171].

Inhibition ntawm ubiquitination los ntawm kev hloov ntawm tag nrho tsib lysine residuesto arginine nyob rau hauv C-terminal fragment ntawm APP (C99) tiv thaiv kom tsis txhob degradation ntawm APP thiab tsub zuj zuj ntawm cov protein nyob rau hauv cov qauv nrog Golgi zoo li tsos. Qhov no yog vim qhov tsis muaj peev xwm ntawm endoplasmic reticulum-associated degradation. Lub C99 undergoescleavage los ntawm -secretase los tsim A [172].

Kev hloov pauv ntawm peb lysine residues (Lys-724, Lys-725, thiab Lys-726) ib txhij ua rau cov protein khaws cia hauv qhov limitingmembrane ntawm endosomes es tsis txhob ua internalized rau hauv intraluminal vesicles ntawmMVBs [173 ]. Thaum tag nrho tsib lysine residues tau hloov pauv los tiv thaiv ubiquitination, cov protein tsis tau zoo txheeb rau MVB / exosomes, thiab kev xaiv nce hauv A 40 tau soj ntsuam [174].

Qhov kev tshawb pom no yog piv rau qhov muaj A 40 hauv amyloid depositsin cerebral amyloid angiopathy [175]. Thaum nws pom tseeb tias ubiquitination ntawm APP yuav coj cov protein mus rau MVB / exosomes, cov pov thawj ncaj qha siv cov kab lis kev cai neuronal lossis hauv vivomodels yuav tsum tau ua pov thawj tias APP, A, lossis A oligomers yog monoubiquitinated rau lawv lub hom phiaj rau MVB / exosomes thiab tias lawv tsis yog ubiquitinated. yuav tsum tau tsom rau forendoplasmic reticulum-associated degradation (ERAD).

Lwm cov kab mob pathological ntawm Alzheimer's tus kab mob yog txawv txav phosphorylatedtau protein nyob rau hauv neurofibrillary tangles (NFT). Tau yog cytoplasmic protein paub rau stabilizemicrotubules. Cov pov thawj ntau ntxiv qhia tias cov kab mob pathological tau protein tuaj yeem sib kis ntawm cov hlwb, nrhiav cov neeg tau los ua cov sib sau ua ke. Cov ntaub ntawv tsis ntev los no cuam tshuam txog exosomes raws li cov cab kuj ntawm tau protein [176,177].

Kev tshuaj xyuas ntawm tes qhia tias exosomes koom nrog tau pathology pib los ntawm microglial hlwb. Exosomes los ntawm microglia kis tauprotein mus rau neurons. Yuav kom tau txais cov pov thawj kev sim, kev tshawb fawb tau ua nyob rau hauv qhov twg exosome biogenesis raug inhibited los yog microglial hlwb tau depleted ntawm tau. Cov txiaj ntsig los ntawm cov kev tshawb fawb no tau pom qhov txo qis ntawm tau tso tawm hauv cov neurons ib txwm [178].

Cov kws sau ntawv qhia tias microglia phagocytose tau-muaj cytopathic neurons rov ua dua tau los ntawm exosomes yog li incriminating exosomes hauv kev nthuav tawm ntawm Alzheimer's disease. Hauv cov hlwb noj qab haus huv, ntau cov protein kinases thiab phosphatase yog lub luag haujlwm rau phosphorylation thiab de-phosphorylation ntawm tau, feem.

Dysregulation ntawm cov enzymes tseem ceeb no tuaj yeem ua rau cov qauv phosphorylation txawv txav ntawm tau hauv AD. Ib qho kev tshawb fawb tsis ntev los no piv rau cov khoom noj khoom haus exosomal los ntawm Nano-LC-MS/MS. Exosomes tau purified los ntawm tib neeg-induced pluripotent qia cell (iPSC) neurons qhia AD familialA246E mutant daim ntawv ntawm presenilin 1 (mPS1) thiab ib txwm tib neeg iPSC neurons.

Tag nrho ntawm 1117 cov proteins tau txheeb xyuas nyob rau hauv ob pawg exosome thiab 733 cov proteins tau tshwm sim rau ob leeg ntawm exosomes. Ntawm cov protein sib txawv nrog mPS1 yog phosphatase thiab protein kinases thiab lawv cov protein ntau cuam tshuam nrog mPS1 exosomes tau qis qis dua li piv rau kev tswj cov neurons [179].

Tsis tas li ntawd, cov exosomes muaj cov protein sib txawv tsis tuaj yeem tswj cov exosomes. Tshwj xeeb, cov proteins sib txawv yog cov neeg koom nrog hauv cov qauv matrix extracellular thiab kev ua haujlwm tawm tswv yim rau lwm cov txheej txheem rau kev nthuav tawm ntawm tau pathology hauv AD [179].Qhov tseem ceeb ntawm kev tshawb fawb hauv Alzheimer's kab mob tau ua rau cov neurons.

Txawm li cas los xij, kev tshawb fawb tau qhia tias atrophy ntawm astroglia tshwm sim thaum ntxov ntawm cov txheej txheem neurodegenerative. Qhov tsis muaj kev txhawb nqa neuronal los ntawm atrophied astroglia ua rau muaj kev cuam tshuam ntawm kev sib txuas ntawm synaptic, poob ntawm synapses, thiab, qhov tsis txaus ntawm cov neurotransmitter homeostasis.Thaum tom qab theem ntawm Alzheimer's kab mob, astrocytes thiab microglia ua kom qhib tau thiab tso cov kab mob inflammatory thiab cov tshuaj neurotoxic. Cov tshuaj Neurotoxic ua rau muaj mob hauv lub hlwb thiab kev tuag neuronal ua rau atrophy ntawm lub hlwb [180].

Nyob rau theem pib ntawm Alzheimer's kab mob, microglial hlwb tau qhib los ntawm Tus Xov Tooj Zoo li receptor 4 tau txais lub luag haujlwm neuroprotective thiab meej A [181]. Phagocytosis thiab degradation ntawm purified polymorphousbeta-amyloid protein deposits thiab A txuam nrog exosomes tau lees paub tias siv cov kab mob microglial hlwb [182,183]. Curiously, astrocytes tshwm sim los daws cov kab mob microglial ntawm lawv cov haujlwm neuroprotective. Cov xov xwm thiab cov npoj yaig tau pom tias incubation nrog A peptide activated glial hlwb thiab tom qab ntawd ua rau mob [184].

Co-culturing nrog astrocytes los yog culturing nyob rau hauv astrocyte-conditioned nruab nrab-inhibited phagocytic action ntawm microglia. Inhibition ntawm microglial phagocytosis yog qhov tshwj xeeb heev vim tias cov tshuaj kho mob los ntawm fibroblasts tsis cuam tshuam rau microglial phagocytic kev ua haujlwm. Los ntawm cov kev tshawb fawb no, nws pom tseeb tias astrocytes tso tawm cov cim hauv daim ntawv ntawm cov yam ntxwv soluble uas cuam tshuam nrog phagocytic kev ua haujlwm ntawm microglia [182]. Lub luag haujlwm ntawm astrocytes thiab microglia tuaj yeem thim rov qab ua raws li kev mob ntev ntawm microglia.

Ntau qhov kev tshawb fawb ywj pheej ua rau kev txiav txim siab tias exosomes tso tawm los ntawm neurons, astrocytes, thiab microglia ua raws li cov khoom pov tseg thiab nqus cov noob tsis muaj soluble A los txhawb A aggregation uas yog internalized los ntawm microglia rau degradation [185-187]. Qhov kev soj ntsuam no tsis yog qhov xav tsis thoob uas tau saib xyuas kev sib txuas lus intercellular ntawm cov hlwb hlwb (hais luv luv hauv Tshooj 3).

Raws li tau hais ua ntej, A aggregates cuam tshuam nrog glycosphingolipids, ceramide, thiab / lossis GPI-anchored protein PrPc (cellular prionprotein) tam sim no nyob rau saum npoo ntawm exosomes thiab ntawm neurons [185,187]. Neuronal exosomesbind A aggregates zoo dua li piv rau astrocytic los yog microglial exosomesdue rau ntau tam sim no ganglioside GM1 thiab sialylated glycosphingolipids tshwj xeeb tshaj yogtrisialoganglioside GT1 ntawm lawv qhov chaw [188–190]. Astrocytic exosomes yog enriched nrog sphingolipid ceramide [187].

Cov A aggregates khi rau astrocytic exosomesare internalized los ntawm cov neurons thiab raug coj mus rau mitochondria, ua rau mitochondrialclustering thiab ib txhij nce cov fission protein Drp -1 qib. Nyob rau sab nraud ntawm mitochondria, exosomal A tsim ib txoj hauv kev nrog ADP / ATP transporter, voltage-dependent anion channel 1, thiab qhib cov caspases.

Active caspases induce neuritefragmentation thiab nws thiaj li neuronal cell tuag [191].Yuav kom nkag siab zoo dua kev sib cuam tshuam ntawm cov proteins, lipids, thiab RNAin Alzheimer's tus kab mob, cov txheej txheem high-throughput tau siv tsis ntev los no. Cohn thiab cov npoj yaig tau coj 'omics' kev sib koom ua ke los txheeb xyuas microglial exosomes [192].

Hauv qhov kev tshawb fawb no, cov kws sau ntawv tau cais cov microglial exosomes los ntawm parietal cortex ntawm cov neeg mob ntshav qab zib-Alzheimer's kab mob. Lawv tau ua ib qho kev ntsuam xyuas kev sib koom ua ke nrog kev soj ntsuam proteomic, transscriptomic, thiab lipidomic analyses. Lawv siv phom phom proteomics, uas yog hais txog kev txheeb xyuas cov protein hauv qab qhov twg cov proteins yog cov yam ntxwv los ntawm kev soj ntsuam ntawm peptides tso tawm los ntawm cov protein los ntawm proteolysis [193], tsom lipidomics, thiab NanoStringnCounter thev naus laus zis the multiplex nucleic acid hybridization technology [194].

Siv qhov kev sib txuas ua ke no, pab pawg tshawb fawb tau pom qhov txo qis hauv homeostaticmicroglia cov cim P2RY12 thiab TMEM119 thiab nce qib ntawm cov kab mob sib txuas-microglia cov cim FTH1 thiab TREM2. Tsis tas li ntawd, tau cov protein ntau hauv AD hlwb-derivedmicroglial exosomes tau ntau dua qhia tias microglia-derived exosomesappear yog qhov tseem ceeb hauv kev sib kis ntawm tau pathology.

Synaptic thiab neuron-specificproteins kuj tau sib txawv hauv AD hlwb-derived microglial exosomes. Cov kws sau ntawv pom zoo, txawm li cas los xij, tias cov proteins synaptic thiab myelin tshwj xeeb tau raug phagocytosed ua ntej nkag mus rau microglial exosomes. Cov kev soj ntsuam lipidomic tau nthuav tawm cov tshuaj tiv thaiv kab mob proinflammatory thiab muaj peev xwm ua tsis tau zoo hauv acyl-chain remodeling.

Thaum kawg, miRNA koom nrog kev tiv thaiv kab mob thiab cellular senescence signaling txoj hauv kev tau nce hauv AD hlwb-derived microglial exosomes [192]. Cov ntaub ntawv no qhia tias qhov kev hloov pauv tseem ceeb hauv cov molecular muaj pes tsawg leeg ntawm exosomes qhia txog kev hloov pauv hauv microglia raws li adiseased xeev.

Ib lo lus nug tseem ceeb yog qhov twg exosomes txhawb lossis tiv thaiv kev tshem tawm cov proteins uas tsis raug? Tsis tas li ntawd, elucidating cov kev koom tes los ntawm exosomes tso tawm los ntawm cov hlwb sib txawv yuav pab txhawb peb txoj kev nkag siab txog kab mob sib kis.

Parkinson's Disease: Parkinson's disease yog ib qho ntawm feem ntau muaj hnub nyoog txog kev mob hlwb-nws yog feem ntau suav hais tias yog ib qho teeb meem ntawm kev txav mus los, nrog cov tsos mob ntawm kev so tshee, rigidity, bradykinesia, thiab lub cev tsis muaj zog [195].

Ntxiv nrog rau tus kab mob no yog kev paub tsis meej, kev nyuaj siab, thiab kev puas siab puas ntsws [196]. Pathologically, nws yog tus yam ntxwv los ntawm degeneration ntawm nigrostriatal dopaminergic neurons thiab lub xub ntiag ntawm Lewybodies uas muaj misfolded -synuclein protein nyob rau hauv cov neurons ciaj sia. Alpha-synucleinis pom nyob rau hauv ntau lub cev kua xws li cerebrospinal kua thiab plasma [197,198].

Alpha-synuclein pom nyob rau hauv kab lis kev cai nruab nrab thaum lub hlwb qhia -synuclein yog culturedin vitro [199]. Xav txog tias -synuclein tau kuaj pom extracellularly thaum tsis muaj ib qho teeb meem ntawm extracellular sorting teeb liab, cov protein no mus txog qhov chaw extracellular li cas? Ntau tus neeg tshawb nrhiav tau tshuaj xyuas cov txheej txheem ntawm -synuclein secretion nrog rau lub luag haujlwm ntawm exosomes hauv -synuclein secretion thiab pathology.

Thawj qhov qhia tau tias exosomes tiag tiag tuaj yeem koom nrog hauv pathogenesis los ntawm kev kawm hauv vitro ntiav SH-SY5Y hlwb qhia -synuclein. Cov kws sau ntawv tau qhia txog kev tso tawm ntawm cov cellular ntawm -synuclein ntawm exosomes nyob rau hauv calcium-dependentmanner thiab qhia lawv txoj kev koom tes hauv kev sib kis ntawm Parkinson tus kab mob pathology [200].

Ua raws li txoj kev tshawb no, -synuclein-muaj exosomes tau txheeb xyuas los ntawm cov cell sib txawv, cov kua dej cerebrospinal, thiab cov ntshav ntawm cov neeg mob Parkinson's disease [201-203]. Txawm li cas los xij, muaj ntau qhov sib txawv tau tshaj tawm hauv cov kev tshawb fawb sib txawv [204]. Interestingly, tus nqi ntawm -synuclein nyob rau hauv exosomes kuj tsawg raws li piv rau dawb -synuclein kuaj incerebrospinal kua los yog conditioned media.

Kev soj ntsuam ze tau qhia tias -synuclein qhia cov hlwb neuroglioma siv ob txoj hauv kev los tso tawm -synuclein oligomers, ib qho los ntawm exosomes thiab ib qho thib ob, ncaj qha tso tawm dawb -synuclein li oligomers [205].

Txawm hais tias exosomes muaj cov qib qis ntawm -synuclein, exosomes muaj txiaj ntsig zoo hauv kev ua rau lawv cov tshuaj lom ntau dua li cov dawb-synuclein. Alpha-synuclein oligomers tam sim no nyob rau hauv exosomeswere internalized zoo dua los ntawm tib neeg H4 neuroglioma hlwb piv rau dawb-synuclein oligomers [205].

Raws li kev soj ntsuam ntawm qhov kev tshawb fawb no, pab pawg ntawm cov kws tshawb fawb no tau tshaj tawm cov txiaj ntsig zoo sib xws uas siv cov exosomes purified los ntawm cov kua cerebrospinal ntawm cov neeg mob Parkinson. Kev ua tau zoo ntawm exosomal oligomerized -synuclein tau pom nyob rau hauv humanH4 neuroglioma cell kab lis kev cai piv rau dawb -synuclein oligomers [206].

Cov ntaub ntawv pov thawj rau kev tso tawm dawb -synuclein mus rau qhov chaw extracellular lossis kua dej los ntawm kev tshawb xyuas lub luag haujlwm ntawm vacuolar protein sorting 4 (VPS4) hauv kev thauj khoom -synuclein tomultivesicular lub cev. Nquag, VPS4 tswj cov kev faib cov proteins mus rau multivesicularbodies. Hauv Parkinson tus kab mob, VPS4 qhia -synuclein rau lysosomes rau nws degradation thiab rov ua dua endosomes rau extracellular secretion ntawm -synuclein [207].

Thaum lysosomalfunction raug txwv, tso tawm ntawm -synuclein ntim rau hauv exosomes tau pom los ua kom cov hlwb incultured SH-SY5Y [208]. Lub endosomal feem ntawm -synuclein dim degradationin tej yam kev mob ntawm lysosomal impairment [209].

For more information:1950477648nn@gmail.com