Retinal Thiab Brain Microglia hauv Ntau Yam Sclerosis Thiab Neurodegeneration Part 1

Abstract:

Microglia yog cov kab mob hauv lub cev ntawm lub hauv paus paj hlwb (CNS), suav nrog retina. Zoo li lub paj hlwb microglia, retinal microglia yog lub luag haujlwm rau kev soj ntsuam lub retina, sai sai teb rau ib puag ncig kev hloov pauv los ntawm kev hloov morphotypes thiab kev ua haujlwm. Microglia ua rau cov lus teb inflammatory hauv cov kab mob neurodegenerative, suav nrog ntau yam sclerosis (MS).

Peb lub hlwb yog ib lub cev muaj zog uas muaj ntau yam neurons thiab neural circuits. Kev sib txuas ntawm cov qauv no yog qhov tseem ceeb rau kev nco ua haujlwm li cas. Thaum peb kawm ib yam dab tsi tshiab los yog paub ib yam dab tsi tshiab, lub hlwb khaws cov ntaub ntawv sib xws hauv synapses ntawm neurons. Sij hawm dhau mus, kev sib txuas ntawm synapses tau maj mam ntxiv dag zog, uas yog lub cim xeeb ntev.

Yog tias peb lub hauv nruab nrab lub paj hlwb tsis txaus, nws yuav ua rau peb nco. Qhov piv txwv tshaj plaws yog nco tsis tau hauv cov neeg laus. Tus mob no feem ntau yog vim kev tuag ntawm neurons thiab tsis muaj zog ntawm kev sib txuas ntawm cov neurons vim kev laus. Tsis tas li ntawd, qee cov kab mob neurological kuj tuaj yeem cuam tshuam nrog kev ua haujlwm ntawm lub hlwb, yog li cuam tshuam rau peb lub cim xeeb. Tab sis cov teeb meem no tsis tuaj yeem thim rov qab, thiab cov txheej txheem tshawb fawb tuaj yeem siv los pab txhim kho thiab tiv thaiv kev nco.

Peb tuaj yeem txhawb kev noj qab haus huv hauv nruab nrab ntawm lub paj hlwb thiab txhim kho kev nco los ntawm kev hloov pauv hauv peb txoj kev ua neej. Piv txwv suav nrog kev ua lub cev tsis tu ncua, pw tsaug zog txaus, noj zaub mov zoo, thiab ua kom lub hlwb ua haujlwm. Cov kev ntsuas no tsis tsuas yog pab tswj kev noj qab haus huv ntawm lub cev tab sis kuj txhawb lub hlwb kev noj qab haus huv thiab txo qis cov neurotransmitters, yog li txhim kho kev nco.

Tag nrho cov nyob rau hauv tag nrho, muaj ib tug muaj zog kev twb kev txuas ntawm lub hauv paus paj hlwb thiab nco. Peb yuav tsum xyuam xim rau peb tus cwj pwm ua neej kom peb lub hlwb ua haujlwm zoo li qhov ua tau thiab siv qhov no los ua kom peb nco tau. Nws pom tau tias peb yuav tsum txhim kho peb lub cim xeeb. Cistanche tuaj yeem txhim kho kev nco zoo vim tias cov nqaij muab tshuaj txhuam yog cov khoom siv tshuaj hauv Suav teb nrog ntau yam tshwj xeeb, ib qho yog los txhim kho kev nco. Kev ua tau zoo ntawm cov nqaij minced yog los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog carboxylic acid, polysaccharides, flavonoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv los ntawm ntau txoj hauv kev.

Nyem paub luv luv Memory yuav ua li cas txhim kho

Thaum qhib los ntawm kev ntxhov siab stimuli, retinal microglia hloov lawv cov morphology thiab kev ua ub no, muaj txiaj ntsig los yog teeb meem. Hauv kev tshuaj xyuas no, peb piav qhia txog cov yam ntxwv ntawm CNS microglia, suav nrog cov neeg nyob hauv lub retina, nrog rau kev tsom mus rau lawv cov morphology, ua kom lub xeev, thiab ua haujlwm hauv kev noj qab haus huv, kev laus, MS, thiab lwm yam kab mob neurodegenerative xws li Alzheimer's kab mob, Parkinson's disease, glaucoma, thiab retinitis pigmentosa, los qhia txog lawv cov kev ua ub no. Peb kuj sib tham txog qhov tsis sib haum xeeb hauv cov ntaub ntawv thiab cov kev muaj peev xwm ntawm kev txo qis kev tsis sib haum xeeb yav tom ntej los ntawm kev siv cov qauv txheej txheem, piv txwv li, automated algorithms, kom muaj kev nkag siab ntau dua ntawm qhov kev tshawb fawb zoo siab no.

Ntsiab lus:

Retina; microglia; neurodegeneration; ntau yam sclerosis; retinal microglia; microglia morphotype.

1. Taw qhia

Microglia yog cov neeg nyob hauv lub cev tiv thaiv kab mob glial hlwb ntawm lub hauv paus paj hlwb (CNS). Lawv dynamically hloov mus rau hauv ntau yam morphologies, uas kuj tau txuam nrog tshwj xeeb activation xeev uas tej zaum yuav muaj feem xyuam rau neuroprotective thiab/los yog neurotoxic functions nyob rau hauv teb rau stimuli, raug mob, los yog thuam [1–6]. Cov kev hloov pauv morphological thiab kev ua haujlwm no yog qhov tseem ceeb los txhawb kev noj qab haus huv CNS los ntawm kev txhawb nqa homeostasis [2,7,8]. Txawm li cas los xij, cov pov thawj tshwm sim tau pib qhia txog kev koom tes ntawm microglia hauv cov kab mob uas ua rau microglial tsis ua haujlwm yuav tshwm sim los ntawm cov kab mob thiab / lossis ua rau cov kab mob sib kis tau zoo sib xws [2].

Txawm li cas los xij, qhov tseeb ntawm kev koom tes thiab cov txheej txheem ntawm yuav ua li cas microglia tuaj yeem cuam tshuam kev noj qab haus huv thiab kab mob tsis paub thiab tam sim no raug tshawb xyuas. Lub hom phiaj ntawm qhov kev tshuaj xyuas no yog los sau cov ntaub ntawv ntawm cov yam ntxwv ntawm CNS microglia, suav nrog cov neeg nyob hauv retina, nrog rau kev tsom mus rau lawv cov kev ua haujlwm, morphology, thiab kev ua haujlwm, txog kev noj qab haus huv thiab kab mob. Hauv thawj ntu, peb tau sau cov lus piav qhia dav dav ntawm cov yam ntxwv tseem ceeb ntawm microglia hauv CNS thiab retina.

Peb kuj piav qhia qee qhov kev hloov pauv microglial uas tshwm sim thoob plaws hauv kev loj hlob thiab kev laus. Hauv seem tom ntej no, peb tham txog kev nkag siab tam sim no ntawm ntau yam sclerosis (MS) raws li kab mob autoimmune, qhov tshwm sim tsis zoo ntawm MS, microglia hauv MS, thiab thaum kawg, microglia hauv lwm cov kab mob neurodegenerative. Thaum kawg, peb muab kev nkag siab txog vim li cas thiaj li muaj qhov tsis sib haum xeeb kev tshawb pom txog tus yam ntxwv ntawm CNS thiab retinal microglia. Ntawm no, peb tawm tswv yim sib txawv ntawm kev sim xws li kev siv cov algorithms automated nyob rau hauv lub teeb ntawm kev ua tau zoo dua thiab zoo ib yam.

2. Microglia

CNS yog tsim los ntawm ntau hom hlwb, 5-10% ntawm uas yog microglia, cov kab mob hauv lub cev [9]. Microglia yog thawj zaug xav tias muaj nyob rau hauv quiescent los yog "so" hlwb uas txuas ntxiv soj ntsuam lawv cov microenvironment rau ib qho stimuli lossis raug mob uas yuav ua rau muaj kev phom sij [5]. Hloov pauv, kev tshawb pom tsis ntev los no tau qhia cov lus piav qhia rau lawv cov khoom muaj zog. Microglia tuaj yeem hloov mus rau ntau lub xeev morphological, hu ua morphotypes. Txhua tus morphotype tau raug cuam tshuam rau ntau lub xeev ua kom muaj zog, uas kuj tau cuam tshuam nrog cov haujlwm tshwj xeeb uas yuav tsum tau khaws cia ib puag ncig physiologically "ib txwm" [5].

Thaum microglia tau qhib los ntawm lawv lub xeev so, lawv tuaj yeem sib txawv ntxiv rau ob lub ntsiab lus tseem ceeb: M1 thiab M2 [6]. Txawm hais tias tsis muaj kev nkag siab txog cov txheej txheem tshwj xeeb uas ua rau muaj qhov sib txawv, M1 thiab M2 microglia kuj tau cuam tshuam nrog cov cytokines, chemokines, thiab trophic yam [6]. Pro-inflammatory teb yog txuam nrog "classically" activated M1 microglia, uas txhawb neuroinflammation raws li ib tug teb rau insult los yog raug mob, tsim ib tug neuro-toxic ib puag ncig thiab tshem tawm dysfunctional fragments ntawm cellular khib nyiab [6]. Qhov no yuav tshwm sim los ntawm qhov tshwm sim ntawm qhov mob xws li interleukin-1ß (IL-1ß), qog necrosis factor-alpha (TNFalpha), thiab inducible nitric oxide synthase (iNOS) [6,10] .

Hloov pauv, "hloov" qhib M2 microglia yog lub luag haujlwm tsis zoo rau cov lus teb los tiv thaiv kab mob uas txhawb nqa cov txheej txheem neuroprotective thiab kho dua tshiab [6,10]. Tsis ntev los no, tsawg kawg peb qhov sub-phenotypes ntawm M2 hom (M2a-c) tau pom [11] uas, tshwj xeeb tshaj yog, hom M2a zais cov tshuaj tiv thaiv kab mob xws li IL-10 thiab insulin-xws li. raws li kev loj hlob zoo-1 (IGF-1), txhawb kev tshem tawm cov khib nyiab ntawm tes thiab kev tiv thaiv neuroprotection [6,11,12].

M2b tau hais tias yuav txhawb nqa los ntawm cov kab mob inflammatory xws li IL-1ß thiab lipopolysaccharides (LPS), uas tuaj yeem ua rau muaj kev nthuav qhia ntawm IL-10 [11]. Cov M2b microglia no tau pom tias muaj phagocytic zog hauv lub hlwb ua qauv rau Alzheimer's disease (AD) thiab qhia txog qib siab ntawm CD64 [11]. M2c "tau txais qhov tsis ua haujlwm" los ntawm IL-10 lossis glucocorticoids, ua rau muaj kev nthuav qhia ntawm kev loj hlob yam xws li TGFß [11]. Txawm hais tias qhov sib txawv no, M1 thiab M2 ua kom muaj zog yuav tsum tau ua haujlwm los lav qhov kev tshem tawm ntawm cov hlwb tsis ua haujlwm lossis tsis muaj qhov tsis zoo ntawm cov khib nyiab ntawm tes [6]. M1 microglia feem ntau koom nrog hauv kev tshem tawm cov khib nyiab ntawm tes, thiab cov lus teb inflammatory no yuav tsum tau tswj los ntawm M2 microglia kom tsis txhob muaj qhov mob ntev heev [6].

Feem ntau hauv cov txheej txheem pathological, qhov sib npaug ntawm M1 thiab M2 polarization pom nyob rau hauv ib txwm muaj kev cuam tshuam yuav cuam tshuam [6]. Qhov no tuaj yeem ua rau kev tshem tawm ntawm cov hlwb noj qab haus huv vim qhov mob M1 ntau dhau thiab M20 s dampening nyhuv ntawm M1s yuav dhau los ua kev puas tsuaj ntxiv [6]. Qhov no feem ntau tshwm sim nyob rau hauv cov kab mob neurodegenerative thiab yog li ntawd, qee qhov kev sib tw kho mob uas lub hom phiaj M1 thiab M2 polarization tau raug npaj [13]. Txawm li cas los xij, tseem muaj cov pov thawj tshwm sim uas qhia tias M1 / ​​M2 polarization yuav dhau los. Nws yog thawj zaug qhia thiab siv los ua kom yooj yim txoj hauv kev ntawm kev txhais cov ntaub ntawv [14].

Txawm li cas los xij, kev nce qib thev naus laus zis tsis ntev los no tau nthuav tawm cov yam ntxwv sib tshooj ntawm morphological thiab genetic yam ntxwv ntawm M1 / ​​M2 hom, qhia tias yuav tsum tau rov ntsuas cov hom microglia [14]. Tsis ntev los no, cov kab mob sib txuas nrog microglia (DAM) kuj tau lees paub tias yog hom microglia tshwj xeeb pom hauv kab mob [14]. DAMs yog tus cwj pwm los ntawm microglia uas qhia txog qib qis ntawm cov neeg soj ntsuam thiab homeostatic genes thiab qib siab ntawm cov cim cuam tshuam nrog degeneration xws li ua rau cov receptors qhia ntawm myeloid hlwb 2 (TREM2) [14,15].

Hais txog morphology, muaj txog tsib lub ntsiab microglial morphotypes uas tau lees paub, suav nrog ramified, hyper-ramified, activated, amoeboid, thiab pas nrig hom. Nyob rau hauv cov xwm txheej uas tsis yog-primed lossis "tsis ua haujlwm", microglia tshwm "ramified". Lawv raug faib sib npaug zoo li "mosaic", nrog rau txhua qhov muaj lub cev me me thiab puag ncig lub cev uas txuas nrog ntau cov txheej txheem nyias thiab ntev uas txuas ntxiv thiab thim rov qab los pab txhawb lawv txoj haujlwm saib xyuas (Daim duab 1) [2,5,16] .

Kev sim hauv vivo cov duab ntawm lub hlwb tau pom tias cov txheej txheem dynamic tuaj yeem sib thooj nrog cov neurons, glia, thiab cov hlab ntsha, qhia tias microglia nquag koom tes nrog lwm qhov chaw ntawm lub cortex kom txhawb nqa lub cev ib puag ncig CNS [17]. Qee lub sij hawm, ramified microglia tuaj yeem paub txog kev hloov pauv ntawm microenvironmental thiab teb los ntawm kev hloov mus rau "hyper-ramified" microglia feem ntau txhais los ntawm ntau cov txheej txheem uas ntev dua thiab tuab dua, txuas nrog lub cev loj, lobular, thiab irregularly zoo li lub cev ntawm tes (Daim duab 1) [16,18 ]. Feem ntau hom primed "non-ramified" microglia, suav nrog cov hlwb hyper-ramified, tau tawg nyob rau hauv CNS nyob rau hauv ib qho tsis xwm yeem thiab "clustered" faib [2].

Hyper-ramified microglia kuj tseem tuaj yeem hloov mus rau hauv daim ntawv qhib thaum raug cuam tshuam rau cov stimuli tsis zoo, uas kuj muaj lub cev zoo sib xws rau cov hlwb hyper-ramified thaum muaj cov txheej txheem tsawg dua uas tuab thiab luv dua (Daim duab 1) [2,16,19] . Thaum tsis muaj tshuaj lom stimuli tau ntev ntev, activated microglia yuav morph mus rau hauv lub xeev "amoeboid" nrog ib tug rounder, loj dua, thiab ntau niaj hnub zoo li lub cell thiab ntau heev los yog tsis muaj dab tsi (Daim duab 1) [16,18]. Ib tug tsis ntev los no rov nrhiav pom morphotype yog "qhib" microglia tus cwj pwm los ntawm lub cev ntev, hnyuv ntxwm-zoo li lub cev ntawm tes nrog ob peb txheej txheem uas tej zaum yuav tsis tas mus li ntev ntawm ramified microglia (Daim duab 1) [20,21].

Txawm hais tias cov pov thawj tshwm sim tau pom cov pas nrig microglia nyob ze ze ntawm cov neurons thiab kho lawv tus kheej raws cov paj hlwb, lawv txoj haujlwm tseem ceeb tseem tsis tau pom [20–23]. Hom kawg yog amoeboid microglia, feem ntau hu ua phagocytic hom uas txav mus rau qhov chaw ntawm kev puas tsuaj thiab phagocytoses tuag los yog tuag neurons thiab cov khib nyiab ntawm tes (Daim duab 1) [5,24]. Tsis ntev los no cov pov thawj tshwm sim tau coj mus rau ib txoj kev xav tias hyper-ramified, activated, thiab rod morphotypes tej zaum yuav "hloov" cov ntaub ntawv uas muaj nyob nruab nrab ntawm lub xeev ramified thiab amoeboid [5,25].

2.1. Retinal Microglia

Lub retina yog ib feem tseem ceeb ntawm CNS. Vim nws cov pob tshab rau lub teeb, nws muaj peev xwm siv tsawg invasive thiab high-resolution imaging modalities kom pom lub retina [26,27]. Nws yog feem ntau paub txog nws txoj kev koom tes hauv kev hloov lub teeb lub zog rau hauv cov teeb liab hluav taws xob [28]. Hauv tib neeg, retina tsim los ntawm thawj lub hlis embryologically mus rau qhov kawg ntawm thawj xyoo, pib los ntawm neuroectoderm [28,29]. Lub retina muaj ntau txheej txheej nrog cov txheej sab hauv tshaj plaws yog cov paj hlwb retinal fiber ntau txheej (RNFL), tom qab ntawd ganglion cell txheej (GCL), txheej txheej plexiform (IPL), sab hauv nuclear txheej (INL), txheej txheej plexiform. (OPL), txheej txheej txheej txheej nuclear (ONL) thiab txheej kawg ntawm cov xim pleev xim rau lub ntsej muag epithelium (RPE) (Daim duab 2) (29]. Thoob plaws hauv cov txheej txheem no muaj ntau hom hlwb, suav nrog cov hlwb amacrine, Muller cells, astrocytes, kab rov tav hlwb. , pas nrig thiab lub khob hliav qab photoreceptors, thiab cov hlwb bipolar, tag nrho cov no kuj tuaj yeem pom nyob rau hauv seem ntawm CNS [29].

Kwv yees li ntawm 0.2% ntawm tag nrho cov hlwb retinal yog tsim los ntawm microglia, ntawm uas 50% feem ntau nyob hauv IPL thaum tus so nyob hauv OPL (Daim duab 2) [2]. Los ntawm txoj kev loj hlob thiab homeostasis, microglia dynamically txav mus los ntawm cov txheej txheem sib txawv ntawm retina, txawm hais tias zam ONL [2]. Tsis tas li ntawd, ntau cov kab mob hauv lub qhov muag thiab cov qauv kev raug mob ntawm lub qhov muag tau pom tias microglia tuaj yeem txav mus rau thaj tsam ntawm degeneration, ua kom muaj zog thiab loj hlob [30,31], raws li tau piav qhia hauv qab no. Txawm hais tias ob qho tib si retinal thiab lub hlwb microglia yog tsim los ntawm cov yolk sac thaum ntxov, qhov tsos ntawm txhua tus morphotype yuav txawv nyob ntawm thaj tsam ntawm CNS [10].

Piv txwv li, microglia nyob rau hauv lub striatum, hippocampus, thiab frontal cortex muaj lub cev loj ntawm tes nrog ntau txheej txheem piv rau cov nyob rau hauv lub cerebellum [32]. Tsis tas li ntawd, muaj pov thawj tias cov txheej txheej ntawm lub paj hlwb cortex muaj microglia ntawm ntau qhov sib txawv [32]. Cov tsos mob ntawm morphotype kuj tseem txawv nyob ntawm cov kev siv los yog cov axes ntawm kev txiav. Piv txwv li, ramified microglia tej zaum yuav tshwm sim kab rov tav ramified, uas, nyob rau hauv ib tug cross-sectional soj ntsuam, tshwm raws li ib tug kab rov tav ntawm tes nyob rau hauv ib tug tag nrho-mount kev soj ntsuam, tshwm li thiab zoo li yav tas los tus qauv morphological piav qhia ntawm ramified microglia [2,33 ].

Thaum microglia yog primed thiab dhau los ua hyper-ramified, lawv cov txheej txheem txuas ntxiv radially, ncav cuag cov txheej txheem sib txawv, uas pom pom ntau dua hauv kev sib cais ntawm cov ntu ntu piv rau kev soj ntsuam tag nrho [2,33]. Txawm hais tias muaj qhov sib txawv no, cov retinal thiab hlwb microglia tau pom los qhia txog ntau yam kev hloov pauv [2]. Ntau cov kev tshawb fawb kuj tseem tuaj yeem soj ntsuam txhua tus morphotype hauv ob lub hlwb thiab retina [2,4,5,22,33,34]. Txawm li cas los xij, nws tseem tsis tau paub meej tias lossis tsis yog txhua tus morphotype hauv ob cheeb tsam CNS qhia tib yam [2].

2.2. Molecular Markers thiab Stimuli cuam tshuam rau Microglial Morphology

Zoo ib yam li lub hlwb, ib tus neeg microglia morphotypes nyob rau hauv lub retina tej zaum yuav tshwm sim los ntawm microglial cov lus teb rau ntau yam cytokines, chemokines, los yog kev puas tsuaj-txo cov qauv molecular nyob rau hauv nws microenvironment, tawm tswv yim heterogeneity nyob rau hauv microglial genetic qhia [9]. Piv txwv li, ramified microglia tau hais tias muaj kev qhia siab ntawm P2RY12, uas feem ntau cuam tshuam nrog kev soj ntsuam kev ua haujlwm, thaum amoeboid microglia tau pom los qhia txog qib siab ntawm CD68 - ib qho tsis zoo ntawm phagocytosis [35,36].

Cov kev qhia sib txawv ntawm microglial ion channels thiab cov receptors saum npoo tuaj yeem cuam tshuam nrog cov molecules (xws li cytokines) hauv microglial microenvironment, uas ua rau muaj kev hloov pauv microglial nrog rau qhov ntom ntom, spatial faib, ua kom lub xeev thiab morphotype, thiab kab mob pathogenesis [9,37]. Piv txwv li, kev hloov pauv kev loj hlob beta (TGFß) yog ib qho tseem ceeb microglial cytokine, pleiotropically koom nrog hauv kev loj hlob ntawm lub cev ntawm cov hlab ntsha thiab cov hlab ntsha [37]. Ma et al., pom iba-1 zoo microglia, los ntawm tag nrho-mounted retinas ntawm tamoxifen-induced ablation ntawm TGFßR2 (TGFß receptor) hauv 2-hli-laus Cx3cr1CreER/+, Tgfbr2flox/flox nas [37 ].

Lub microglial morphology tshwm sim nyob rau hauv 1 hnub tom qab TGFßR2 ablation (PTA), uas tom qab ntawd los ua tsawg ramified nrog cov txheej txheem "stubby" los ntawm 2-5 hnub PTA thiab thaum kawg tshwm sim nrog cov txheej txheem ntev uas tau ua raws li cov hlab ntsha retinal los ntawm 3-10 lub lis piam. PTA [37]. Real-time polymerase saw cov tshuaj tiv thaiv (RT-PCR) kev soj ntsuam ntawm TGFßR2 ablated retinal microglia tau qhia txog kev txo qis ntawm kev loj hlob yam tseem ceeb (xws li BDNF, PDGFA) thiab nce kev qhia ntawm cov cim ua kom mob (piv txwv li, MHCII, CD68). Qhov no tsis pom zoo hauv kev noj qab haus huv microglia.

Tsis tas li ntawd, thaum TGFßR2 ablated tsiaj tsis pom muaj kev cuam tshuam rau lub retinal vasculature, lawv tau ntsib retinal thinning thiab amplified tus nqi ntawm pathological choroidal neovascularisation teb rau kev raug mob [37].

2.3. Extracellular Vesicles: Cov teebmeem ntawm Microglia

Retinal (thiab lub hlwb) microglia kuj tso tawm cov hlwv extracellular (EVs), uas yog cov kab mob sib txuas ua ke ntawm mRNA, miRNA, DNA, cytokines, lipids, thiab cov proteins, suav tias yog biopsy ntawm nws lub hauv paus cell [6,38,39] . EVs koom nrog hauv kev sib txuas lus ntawm tes-rau-cell los ntawm kev thauj lawv cov neuro-tiv thaiv / tshuaj lom hauv cov lus teb rau intracellular thiab extracellular cues thaum lawv txav mus los ntawm cov hlab ntsha thiab cov kua cerebrospinal (CSF) mus cuag lwm cov hlwb nyob ze thiab nyob sib ze [6, 38, 39] ib.

EVs include exosomes and exosomes, which consist of apoptotic bodies and microvesicles [39]. Firstly, many endosomal vesicular bodies fuse to form exosomes (40–160 nm in size) which are then released for intercellular communication [39]. Secondly, microvesicles instead originate from the plasma membrane undergoing outward budding (100–1000 nm) [38]. Finally, apoptotic bodies are >1000 nm loj thiab daim ntawv los ntawm daim nyias nyias blebbing ntawm disintegrating, piv txwv li, retinal microglia [38]. Cheebtsam ntawm apoptotic lub cev xws li phosphatidyl serine modulate microglial phagocytosis [38,39]. Raws li qhov tshwm sim ntawm cov yam ntxwv sib txawv no, microglial EVs tsis ntev los no tau pib tshawb xyuas cov kab mob neurodegenerative.

2.4. Microglia thiab Aging

Microglial hlwb nyob rau hauv lub retina ntawm cov me nyuam mos thiab postnatal nas muaj ib puag ncig los yog amoeboid daim ntawv thiab qhia pseudopodal txheej txheem koom tes nyob rau hauv cell debris phagocytosis thiab kev loj hlob synapse remodeling [2]. Tsis tu ncua, raws li lub lim tiam thib ob thiab thib peb ntawm lub sijhawm tom qab yug me nyuam, microglial cell lub cev ua me me nrog cov txiaj ntsig zoo [2], piv txwv li cov phenotype zoo heev nrog kev txhim kho hauv hlwb [40]. Qhov kev vam meej no kuj tau tshwm sim hauv cov cheeb tsam hauv lub hlwb, suav nrog cerebellum, uas qhia tias microglia koom tes los ntawm kev loj hlob ntawm CNS.

Cov kev tshawb fawb tshawb xyuas cov yam ntxwv micoglia microglia hauv cov laus (24 hlis) thiab cov nas laus) kom pom cov pawg tsawg thiab tsis xwm yeem faib pawg [41]. Txawm li cas los xij, kev tshawb fawb ntawm retinal microglia tau qhia qee qhov kev sib cav sib ceg.

Ua ntej, cov pab pawg hnub nyoog zoo sib xws ntawm cov nas raws li txoj kev tshawb fawb dhau los tau kuaj xyuas (18-24 lub hlis vs. 3-4 lub hlis) kom pom tias cov neeg laus muaj qhov nce siab ntawm cov retina microglia densities piv rau cov nas cov laus [42]. Qhov no qhia tau tias cov lus teb microglial rau kev laus tuaj yeem yog thaj tsam tshwj xeeb. Kev tshuaj xyuas ntxiv ntawm lub sijhawm tiag tiag ntawm retinal imaging tau pom tias feem ntau ntawm cov laus cov neeg laus microglia tshwm sim muaj cov txheej txheem tsawg dua thiab luv dua, qhia txog kev ua kom muaj zog lossis amoeboid microglia, dua li cov nas hauv cov nas me [42].

Cov no tau pom tias tau npaj rau hauv kev faib khoom mosaic. Ib txoj kev tshawb fawb tsis ntev los no tau saib ntawm qhov sib txawv ntawm cov morphological thiab cov cim qhia qhov sib txawv ntawm tag nrho-mounted retinal microglia hauv cov laus (15 lub hlis) thiab cov hluas (hnub nyoog tsis tau teev) nas [43]. Tsis zoo li cov txiaj ntsig los ntawm Damani et al., txoj kev tshawb no pom tsis muaj qhov sib txawv tseem ceeb hauv iba-1 qhov zoo ntawm cov retinal microglia cell ceev thiab thaj chaw uas muaj cov txheej txheem ntawm ob pawg hnub nyoog, thaum lub cell soma cheeb tsam hauv OPL, IPL, NFL, thiab GCL thiab cov txheej txheem ntsug tau nce ntau [42,43].

Tsis tas li ntawd, cov tub ntxhais hluas microglia hlwb feem ntau qhia P2RY12 thiab tsis muaj CD68, thaum lub hnub nyoog microglia yog CD68+ thiab tshwm sim amoeboid [43]. Cov txiaj ntsig no, hloov pauv, txhais tau hais tias nrog kev laus, microglia tuaj yeem hloov pauv lawv cov morphologies thiab caj ces profile kom haum rau cov txheej txheem kev laus [43]. FernándezAlbarral li al., Txawm li cas los xij, tsis txhob nthuav tawm cov hnub nyoog pes tsawg, hom nas, lossis cov kev siv ntau npaum li cas. Qhov sib txawv ntawm cov kev tshawb fawb no tuaj yeem cuam tshuam cov txiaj ntsig.

Cov laus microglia ua tsis tshua muaj zog, qhia cov txheej txheem qeeb qeeb piv rau cov neeg hauv lawv cov menyuam yaus, uas yuav cuam tshuam lawv lub peev xwm los tshawb fawb txuas ntxiv thiab cuam tshuam nrog lawv ib puag ncig [42]. Post-mortem hippocampal thiab cortical kev tshawb nrhiav hauv "cov tub ntxhais hluas", "nrab", lossis "laus" (20–69 vs. 70+ vs. 90+} xyoo) cov neeg laus tau tshaj tawm cov lus teb tshwj xeeb hauv cheeb tsam microglial rau laus [4]. Qws-zoo li microglia tau pom tias muaj ntau dua nyob rau hauv "nruab nrab" piv rau "cov tub ntxhais hluas" cov neeg laus, txawm hais tias qhov no tsuas yog pom hauv hippocampus thaum cov laus "laus" tsuas yog muaj cov pas nrig loj hauv hippocampus [4]. Lwm cov kev tshawb fawb cortical thiab hippocampal pom zoo li microglial tiam sis nrog lub hnub nyoog, uas qhia tias muaj hnub nyoog microglia tuaj yeem txo qis kev soj ntsuam lub peev xwm xav tau los tswj kev noj qab haus huv CNS, uas tuaj yeem ua rau muaj kev pheej hmoo ntawm kev tsim cov kab mob neurodegenerative [44-46].

Lub myelinated axons ntawm neurons yog ib qho tseem ceeb ntawm CNS uas ua rau muaj txiaj ntsig zoo ua tau zoo [47]. Whilst myelin yog tsim los ntawm ntau lub hlwb oligodendrocyte, nws tau ua haujlwm tas li, nrog cov khib nyiab myelin raug tshem tawm ncaj qha thiab hloov tsis ncaj los ntawm microglia [47,48]. Txawm li cas los xij, nws tau raug pom zoo tias kev hloov pauv hauv myelin khib nyiab tsim nrog kev laus kuj tuaj yeem ua rau muaj hnub nyoog ntsig txog kev ua haujlwm tsis zoo ntawm CNS lub cev tiv thaiv kab mob xws li microglia [49]. Vim li no, nrog rau hnub nyoog, muaj ntau dua myelin-txuas molecules impaired, thiab ntau dua myelin protein turnover tus nqi yuav tsum tau [49].

Qhov no ua rau muaj qhov nce ntxiv ntawm myelin kev puas tsuaj, ua rau lub nra hnyav ntawm myelin tsub zuj zuj, uas tom qab ntawd tsim cov lysosomal aggregates hauv microglia hlwb [49]. TREM2 yog qhia rau ntawm microglial cell daim nyias nyias; Txawm li cas los xij, nws qhov tsis txaus lossis kev hloov pauv tuaj yeem ua rau muaj kab mob tshwm sim los ntawm demyelination ntau dhau [50]. Poliani et al. pom "laus" TREM2 lub hlwb tsis txaus muaj demyelination nrog dystrophic thiab amoeboid-zoo li microglia [50]. Nws tseem tau hais tias TREM2-zoo amoeboid microglia yuav ces morph mus rau hauv cov duab sib txawv raws li nws pib tsim yam xws li TNF thiab IL-1, uas yog suav tias yog "pro-regenerative" yam [48 ].

Yog li, lub extracellular matrix yog hloov los ua kom hloov cov extracellular matrix kom nyiam thiab qhib oligodendrocyte precursor hlwb (OPCs) uas ces remyelinate axon [48]. Tsis tas li ntawd, kev noj qab haus huv microglial cov lus teb rau demyelination tau pom los ua kom muaj kev qhia cov noob cuam tshuam nrog kev ua kom muaj zog, phagocytosis, thiab lipid metabolism, thaum TREM2 tsis txaus microglia tau pom tsis yog [50]. Lwm cov kev tshawb fawb tau pom tias txawm hais tias cov khib nyiab tshem tawm los ntawm microglial phagocytosis tseem ceeb dua nrog kev nce hauv lub hnub nyoog, "hnub nyoog" myelin phagocytosis tau paub ntau dua nrog "laus" myelin [51]. Cov kev hloov pauv hnub nyoog no kuj muaj feem cuam tshuam nrog qhov tshwm sim ntau zaus ntawm "dystrophic" non-ramified microglia [51]. Tseem tsis tau muaj ntau qhov kev tshawb nrhiav ntawm myelin khib nyiab cuam tshuam txog retinal microglial phagocytosis, tej zaum vim tsis muaj myelin hauv retina nws tus kheej.

Nrog kev laus, cov neeg microglial ua dystrophic thiab raug hloov pauv ntawm cov qauv thiab morphological. Lub cytoplasm pib tawg, thiab lawv cov txheej txheem ntawm tes maj mam poob qhov zoo ramifications thiab qhia spheroidal o [52]. Tsis tas li ntawd, lawv cov kev ua haujlwm microglial pib poob qis thiab qhia qhov txawv txav microglial raug mob teb. Cov kev hloov pauv no, ua ke nrog cov molecular thiab noob qhia kev laus hloov pauv hauv microglia, ua rau lawv txo qis peev xwm tswj hwm homeostasis hauv lub cev tiv thaiv kab mob, thiab qhov no yuav ua rau muaj kev puas hlwb neuronal, kev txawj ntse poob, thiab cov kab mob muaj hnub nyoog [5,27,53– 55] ib.

2.5. Genetic Factors: Cov teebmeem ntawm Kev Laus Microglia

Hnub nyoog yog qhov muaj txiaj ntsig zoo rau cov kab mob neurodegenerative [56–58]. Yog li ntawd, kev hloov pauv ntawm cov noob qhia hauv cov laus retina tau dhau los ua qhov kev txaus siab tseem ceeb. Piv txwv li, Chen et al. tshawb xyuas tag nrho cov retinal RNA ntawm 3- hli- thiab 20- hli-laus C57BL/6 nas [57]. Nrog rau lub hnub nyoog nce, 298 noob, suav nrog cov uas cuam tshuam txog kev ntxhov siab thiab glycoprotein synthesis, tau tswj hwm ntau dua li ob zaug thaum 137 cov noob, suav nrog cov lus teb rau kev tiv thaiv kab mob thiab tiv thaiv, kuj tau raug txo qis ntau dua ob zaug [57. ].

Tsis tas li ntawd, RT-PCR kev soj ntsuam pom tau nce hauv inflammatory cytokine-, chemokine-, los yog ntxiv cov noob caj noob ces, piv txwv li, chemokine (CC motif) ligand 2 (CCL2), CCL12 lossis ntxiv cov khoom xyaw 3 (C3) [57]. Cov kws sau ntawv tau xav tias qhov no yuav cuam tshuam txog kev ua kom microglial, uas tau txhawb nqa los ntawm kev soj ntsuam immunohistological ntawm isolectin B4+ amoeboid microglia hauv IPL ntawm cov nas muaj hnub nyoog nkaus xwb [57]. Lwm txoj kev tshawb nrhiav tau tshwj xeeb los tshawb xyuas cov kev hloov pauv hauv cov laus retinal microglia los ntawm kev sib piv RNA muab rho tawm los ntawm kev cais cov retinal microglia ntawm 3-, 12-, 18-, thiab 24- hli- qub C57BL/6 nas [58].

Tag nrho ntawm 719 qhov sib txawv ntawm cov noob tau txheeb xyuas thiab tau ua haujlwm cuam tshuam nrog microglial kev tiv thaiv kab mob, xws li IL3 thiab IL7, angiogenesis, xws li vascular endothelial kev loj hlob yam, thiab trophic kev loj hlob yam, xws li, neurotrophin [58]. Interestingly, zoo li Chen li al., kev qhia ntawm C3, ib tug gene cuam tshuam nrog lub hnub nyoog-txog macular degeneration (AMD), nce nrog lub hnub nyoog uas implied tias senescence-cuam tshuam retinal microglia transcriptional hloov pauv yuav ua rau AMD pathogenesis [58].

3. Ntau yam Sclerosis

3.1. Ntau Sclerosis

Multiple Sclerosis (MS) yog ib tus kab mob mob ntev ntawm CNS, cuam tshuam txog 100,000 cov neeg mob hauv tebchaws Askiv thiab 2,500,000 cov neeg mob thoob ntiaj teb [59]. Interestingly, nws tuaj yeem cuam tshuam txog li peb zaug ntau tus poj niam li txiv neej, nrog rau qhov nruab nrab hnub nyoog pib thaum ntxov laus [60]. Txawm hais tias thawj cov ntaub ntawv ntawm cov kab mob pathophysiological ntsig txog MS hnub rov qab mus rau xyoo 1838, lawv cov kev nthuav qhia pathological thiab kev kho mob tau pom thawj zaug "MS" hauv 1863 los ntawm Jean-Martin Charcot [61].

Txij thaum ntawd los, lub complex pathologies ntawm MS tau tshwm sim. Cov tsos mob tshwm sim ntau zaus ntawm MS koom nrog txoj hauv kev ntawm lub qhov muag xws li RNFL thinning, optic neuritis (ON) tus cwj pwm los ntawm kev puas tsuaj rau lub paj hlwb, thiab uveitis tshwm sim los ntawm intraocular o ntawm lub cev vitreous, retina, thiab uveal tract [62-66]. Nws kuj tau raug tshaj tawm tias qhov kev hloov pauv ntawm lub retinal tuaj yeem tshwm sim ua ntej kev hloov pauv ntawm tus so ntawm CNS hauv ntau cov kab mob neurodegenerative, suav nrog MS [26].

Cov kev tshawb pom tsis ntev los no tau ua rau muaj kev txaus siab ntau rau kev tshawb fawb txog retinal. Txawm hais tias muaj cov txheej txheem nyuaj koom nrog hauv MS txoj kev loj hlob, nws yog ib qho kab mob uas txhais los ntawm cov lus teb autoimmune los ntawm kev ua kom lub cev tiv thaiv kab mob xws li T-lymphocytes, B-lymphocytes, microglia hlwb thiab macrophages, demyelination, remyelination thiab neurodegeneration [12,67-69].

Ib qho kev lees paub zoo ntawm MS yog tias nws txhim kho los ntawm ob theem tseem ceeb. Ua ntej, T-cells thiab B-cells kho cov lus teb inflammatory los ntawm kev tso cov cytokines uas ua rau cov kab mob inflammatory xws li microglia tom qab "kaw" ntshav-hlwb barrier (BBB) ​​[68,70–72]. Cov mob o tuaj yeem ua rau mitochondrial tsis ua haujlwm, ua rau lub zog tsis muaj zog. Qhov thib ob, cov teeb meem neuroprotective yog overridden, uas cuam tshuam lub peev xwm kho demyelination, puas axons, thiab neurodegeneration [68,70]. Raws li qhov tshwm sim, muaj qhov cuam tshuam loj ntawm axonal conductance qhov twg thaum kawg, tus neeg mob tau tso tseg nrog qhov tsis tuaj yeem rov qab los ntawm CNS xws li BBB, ua rau nws dhau los ua "tawg" [68]. Qhov no, txawm li cas los xij, tseem yog ib txoj kev xav vim muaj pov thawj tshwm sim tsis ntev los no qhia tias qee cov neeg mob teb tau zoo dua rau cov kws kho mob uas tsom B-hlwb tsis zoo rau cov uas tsom T-cells [70]. Txawm hais tias muaj ntau qhov kev tshawb nrhiav uas siv cov kev hloov pauv mus tas li, tsis muaj kev pom zoo vim qhov tsis sib xws ntawm cov txiaj ntsig kev tshawb fawb [73].

3.2. Sub-types of Multiple Sclerosis

Muaj ib qho spectrum ntawm qhov hnyav rau cov tsos mob thiab tus nqi ntawm kev loj hlob, xav txog qhov heterogeneity ntawm MS [70]. Qhov kev nthuav qhia ntxov tshaj plaws ntawm cov neeg mob MS tuaj yeem lees paub tias yog qhov chaw kho mob cais tawm (CIS) [67]. CIS cov neeg mob muaj monophasic thiab mono-focal symptomatic lub sijhawm, muaj, piv txwv li, ataxia, photophobia, lossis areflexia, uas kav li ntawm 24 teev ntawm 3 lub lis piam [67]. Thawj qhov kev nce qib MS (PPMS) cuam tshuam txog li 15% ntawm cov neeg mob MS uas feem ntau muaj kev poob qis hauv kev noj qab haus huv [74]. Progressive relapsing MS (PRMS) yog hom tsawg tshaj plaws ntawm MS, uas tsuas yog cuam tshuam txog li 5% ntawm cov neeg mob uas muaj kev poob qis hauv kev noj qab haus huv nrog kev npaj txhij txog ntawm kev puas tsuaj thiab rov qab los [74]. Relapse remitting MS (RRMS) yog ib daim ntawv ntau dua, cuam tshuam rau 80-90% ntawm cov neeg mob uas muaj kev tsis taus uas tsis tau pom dua [70].

Feem ntau, cov surges no tau ua tiav los ntawm kev rov ua kom tiav, tab sis raws li cov neeg mob hnub nyoog thiab nce mus rau theem tom qab, cov kev rov qab los ua ntau dua [70,74]. Qhov no tuaj yeem ua rau muaj kev ncaj ncees los ntawm ntau tus neeg mob RRMS uas tab tom tsim kho cov kab mob MS (SPMS), qhov twg cov neeg mob yuav ntsib kev tsis zoo ntawm cov kab mob tsawg dua thiab pib ua cov kab mob ntawm PPMS [70,74]. Tsis ntev los no, kev txaus siab ntau dua hauv kev tshawb nrhiav caj ces tau ua rau MS-tshwj xeeb alleles thiab cov noob hloov pauv tau lees paub, tshwj xeeb tshaj yog los ntawm kev tshawb fawb genome-wide Association [70,75]. Cov ntaub ntawv loj loj tau ua raws li kev soj ntsuam ntau dua uas tau qhia tias cov noob caj noob ces muaj feem cuam tshuam rau ntau hom MS [76]. Cov noob variants no feem ntau pom lub cev thiab ua haujlwm nyob ze rau cov noob tshuaj immunomodulatory cuam tshuam nrog MS pathogenesis [70,75].

Txawm li cas los xij, cov ntaub ntawv ntawm cov subtypes no tsuas yog piav qhia vim tias tsis muaj pov thawj txaus los ua qhov tseeb ntawm qhov sib txawv ntawm pathophysiological [77]. Piv txwv li, feem ntau ntawm cov neeg mob MS tau ntsib cov theem asymptomatic uas yog MS-txuas nrog cov kab mob thiab lwm yam kev hloov pauv pathophysiological yuav tshwm sim ntsiag to [78]. Qee qhov kev tshawb fawb tom qab lub hlwb tau pom txawm tias muaj cov kab mob sib txawv ntawm MS-txuas nrog cov kab mob pom hauv cov ntsiab lus uas tau suav tias "zoo" thaum lawv lub neej [78]. Tsis ntev los no, cov ntaub ntawv hais txog cov sub-types no tau hloov zuj zus, sib txawv ntawm cov kab mob kev ua haujlwm lossis tsis muaj kab mob ua haujlwm nrog cov ntsiab lus ntawm "surges" lossis kev nce qib tsis tu ncua thiab kev soj ntsuam ntawm cov kab mob CNS tshiab [77].

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