小膠質(zhì)細(xì)胞受體與阿爾茨海默病

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(南華大學(xué)附屬第一醫(yī)院神經(jīng)內(nèi)科，湖南 衡陽(yáng) 421001)

·文獻(xiàn)綜述·

小膠質(zhì)細(xì)胞受體與阿爾茨海默病

謝恒，游詠*

(南華大學(xué)附屬第一醫(yī)院神經(jīng)內(nèi)科，湖南 衡陽(yáng) 421001)

阿爾茨海默病(AD)是一種以認(rèn)知與其它機(jī)能進(jìn)行性減退為主要特征的神經(jīng)系統(tǒng)退行性病變。越來(lái)越多的證據(jù)表明，炎癥反應(yīng)在AD的病理進(jìn)程中起了重要的作用。小膠質(zhì)細(xì)胞為腦內(nèi)固有吞噬細(xì)胞，可表達(dá)多種受體；β-淀粉樣蛋白(Aβ)通過與上述受體的相互作用促進(jìn)小膠質(zhì)細(xì)胞的活化，刺激炎癥反應(yīng)產(chǎn)生。本文就近年來(lái)關(guān)于小膠質(zhì)細(xì)胞受體在AD發(fā)生發(fā)展中的作用作一綜述。

小膠質(zhì)細(xì)胞受體； 阿爾茨海默病； β-淀粉樣蛋白； 炎癥反應(yīng)

阿爾茨海默病(Alzheimer’s disease，AD)是一種以認(rèn)知與其它機(jī)能進(jìn)行性減退為主要特征的神經(jīng)系統(tǒng)退行性病變。隨著社會(huì)發(fā)展，生活方式轉(zhuǎn)變，人口老年化進(jìn)程加速；AD日益成為一個(gè)突出的醫(yī)學(xué)與社會(huì)問題，給家庭與社會(huì)帶來(lái)沉重的負(fù)擔(dān)。據(jù)世界衛(wèi)生組織的統(tǒng)計(jì)，目前全世界超過3500萬(wàn)AD患者，并且這個(gè)數(shù)字仍呈上升趨勢(shì)[1]。AD的特征性病理改變主要包括β-淀粉樣蛋白(Amyloid β-protein Aβ)的沉積導(dǎo)致的老年斑、tau蛋白異常聚集形成纖維纏結(jié)及神經(jīng)元缺失和膠質(zhì)細(xì)胞增生[2]。截止目前，AD的具體發(fā)病機(jī)制尚不是很清楚，可能的機(jī)制包括Aβ級(jí)聯(lián)假說(shuō)、Tau 蛋白假說(shuō)、神經(jīng)血管假說(shuō)、細(xì)胞周期調(diào)節(jié)蛋白障礙、氧化應(yīng)激、炎癥反應(yīng)、線粒體功能障礙等。近年來(lái)愈來(lái)愈多的研究表明,Aβ沉積誘導(dǎo)的炎癥反應(yīng)是導(dǎo)致AD發(fā)生發(fā)展的重要病因；在AD模型動(dòng)物及AD患者腦內(nèi)老年斑周圍及核心均可見大量的小膠質(zhì)細(xì)胞聚集，提示小膠質(zhì)細(xì)胞聚集是對(duì)Aβ沉積的反應(yīng),其機(jī)制可能是通過Aβ與膠質(zhì)細(xì)胞受體結(jié)合而使其激活并表達(dá)相關(guān)細(xì)胞因子，進(jìn)而促發(fā)AD的病理進(jìn)程。本文就Aβ激活小膠質(zhì)細(xì)胞受體誘導(dǎo)的級(jí)聯(lián)反應(yīng)及其在AD發(fā)生發(fā)展中的作用作一綜述。

1 小膠質(zhì)細(xì)胞

小膠質(zhì)細(xì)胞占腦內(nèi)神經(jīng)膠質(zhì)細(xì)胞族群的5%～10%，在正常人的中樞神經(jīng)系統(tǒng)中呈靜息狀態(tài)[3]。在病理?xiàng)l件下，活化的小膠質(zhì)細(xì)胞質(zhì)發(fā)生形態(tài)學(xué)的改變，并產(chǎn)生多種細(xì)胞因子和炎癥趨化因子，從而對(duì)周圍的細(xì)胞產(chǎn)生影響。研究發(fā)現(xiàn)，小膠質(zhì)細(xì)胞可通過清除Aβ沉積、啟動(dòng)吞噬細(xì)胞活性及釋放毒性細(xì)胞介質(zhì)從而在AD發(fā)生發(fā)展進(jìn)程中起著重要的作用。在體外，Aβ可激活小膠質(zhì)細(xì)胞進(jìn)而誘導(dǎo)促炎癥因子的釋放，如白介素類(1L-1、1L-2、1L-6、1L-8)、腫瘤壞死因子(TNF-a)、趨化因子、炎癥因子、活性氧和氮族等，上述促炎癥因子均可導(dǎo)致神經(jīng)元損傷[4-5]。小膠質(zhì)細(xì)胞可表達(dá)多種受體如Toll樣受體、補(bǔ)體受體、Fc受體、清道夫受體、CD36、晚期糖基化終產(chǎn)物受體等[6-7]；這些受體相互協(xié)同共同參與對(duì)Aβ識(shí)別、內(nèi)化與清除及小膠質(zhì)細(xì)胞激活功能。

2 小膠質(zhì)細(xì)胞受體與AD

2.1 Toll樣受體(Toll-like receptors，TLRs)

TLRs是膜蛋白家族一員，可以識(shí)別多種病原體表面各種不同模式分子，是非特異性免疫反應(yīng)中一類重要的模式識(shí)別受體；此外TLRs還可以識(shí)別損傷相關(guān)模式分子。在哺乳動(dòng)物中，目前描述的共有12種TLRs在各種細(xì)胞中表達(dá)，包括小膠質(zhì)細(xì)胞和星形膠質(zhì)細(xì)胞[8-9]。在 APP23轉(zhuǎn)基因AD小鼠腦內(nèi)Aβ斑塊區(qū)域腦組織中可以檢測(cè)到TLR2、TLR4、TLR5、TLR7與TLR9高水平的mRNA的表達(dá)[10]。激活TLRs可觸發(fā)不同的信號(hào)轉(zhuǎn)導(dǎo)通路進(jìn)而導(dǎo)致促炎癥因子的產(chǎn)生，同時(shí)參與Aβ攝取與清除。

TLR4不僅能被脂多糖(Lipopolysaccharide LPS)激活也能識(shí)別多種內(nèi)源與外源性分子。研究顯示，TLR4在小膠質(zhì)細(xì)胞活化過程中發(fā)揮著重要作用；其中Aβ刺激誘導(dǎo)的小膠質(zhì)細(xì)胞活化依賴于TLR4與CD14及骨髓分化蛋白2的功能捆綁。體外實(shí)驗(yàn)表明，經(jīng)LPS激活TLR4的小膠質(zhì)細(xì)胞其對(duì)Aβ的攝取明顯增加；而在脂多糖應(yīng)答缺陷的小鼠體內(nèi)顯示Aβ負(fù)荷增加，表明了TLR4參與了Aβ的清除過程[11]。此外，TLR4基因突變的AD模型小鼠腦內(nèi)Aβ水平明顯升高且表現(xiàn)出空間學(xué)習(xí)能力損傷[12]。最近的一項(xiàng)研究表明，TLR4受體激動(dòng)劑單脂質(zhì)A不僅可誘導(dǎo)小膠質(zhì)細(xì)胞輕微的炎癥反應(yīng)同時(shí)可增強(qiáng)小膠質(zhì)細(xì)胞對(duì)Aβ的攝取，其機(jī)制可能與P38的活化及SR-AI 的表達(dá)相關(guān)[13]。

TLR2同樣參與了Aβ刺激誘導(dǎo)的小膠質(zhì)細(xì)胞活化及后續(xù)的炎癥反應(yīng)。在AD 模型大鼠和AD病人腦中均可見TLR2 mRNA表達(dá)水平顯著增加[14]。TCR2受體缺失的AD模型大鼠表現(xiàn)出空間與非空間記憶損傷[15]。在Aβ刺激條件下，TLR2受體敲除的小鼠小膠質(zhì)細(xì)胞中TNF-α，iNOSβ，IL-1，IL-6、CD68的表達(dá)顯著下調(diào)[16]。此外，Aβ42和TLR2共存于小膠質(zhì)細(xì)胞上，肽聚糖誘導(dǎo)的TLR2激活可增加小膠質(zhì)細(xì)胞對(duì)Aβ的攝取[17]。TLR9是TLRs家族另一個(gè)成員，當(dāng)小膠質(zhì)細(xì)胞受Aβ刺激時(shí)其表達(dá)也會(huì)上調(diào)。TLR9的激動(dòng)劑非甲基化胞嘧啶鳥嘌呤(cytosine phosphate guanine,CpG)可激活小膠質(zhì)細(xì)胞增加其對(duì)Aβ的攝取[18]。側(cè)腦室注射CpG可改善轉(zhuǎn)基因AD模型小鼠認(rèn)知功能損傷[19]。上述研究結(jié)果表明，TLRs在AD的發(fā)生發(fā)展進(jìn)程中扮演著雙重角色；一方面，TLRs激活觸發(fā)的炎癥反應(yīng)可以導(dǎo)致神經(jīng)毒性作用，另一方面，TLRs激活也能促使小膠質(zhì)細(xì)胞對(duì)Aβ攝取進(jìn)而加速Aβ的清除。

2.2 補(bǔ)體受體(Complement receptors，CRs)

補(bǔ)體系統(tǒng)是對(duì)微生物誘導(dǎo)的炎癥反應(yīng)作出免疫應(yīng)答，并使其易感性消退的一類膜蛋白質(zhì)類[20]。在AD病人中若干的補(bǔ)體蛋白與相應(yīng)的mRNA出現(xiàn)了上調(diào)，可能與Aβ誘導(dǎo)的炎癥反應(yīng)、老年斑的形成以及Aβ吞噬過程相關(guān)。補(bǔ)體系統(tǒng)的激活主要有3個(gè)途徑：經(jīng)典途徑、旁路途徑和MBL途徑。Aβ可激活經(jīng)典與旁路途徑導(dǎo)致C3活化、C5a的產(chǎn)生及膜攻擊復(fù)合體的形成。補(bǔ)體系統(tǒng)移除傳染性病原體是通過活化多種受體來(lái)完成的，這些受體包括CR1(CD35)、CR2(CD21)、CR3(CD11b/CD18)、CR4 (CD11c/CD18)和C5aR(CD88和C5L2)。

CR1是一種跨膜受體，主要的作用是調(diào)節(jié)補(bǔ)體的級(jí)聯(lián)反應(yīng)；CR1可以結(jié)合補(bǔ)體因子C3b和C4b。AD 病人腦脊液中可見CR1水平顯著增加[21]。最近一項(xiàng)全基因組關(guān)聯(lián)性研究顯示，CR1突變與遲發(fā)性AD發(fā)生風(fēng)險(xiǎn)密切關(guān)聯(lián)。小膠質(zhì)細(xì)胞的活化可以增加CR1的表達(dá)，而活化的CR1可進(jìn)一步誘導(dǎo)神經(jīng)元的凋亡，其機(jī)制可能與活性氧、TNF-a 和1L-B的生成增加相關(guān)[22]。CR1在紅細(xì)胞上的表達(dá)參與了外周Aβ的清除，提示CR1可能與AD病人Aβ的清除有關(guān)[23]?；蚨鄳B(tài)性研究也顯示了CR1與AD發(fā)生風(fēng)險(xiǎn)之間的關(guān)聯(lián)[24]。

補(bǔ)體因子C3 是補(bǔ)體系統(tǒng)的重要成份，通過與CR3的相互作用誘導(dǎo)對(duì)病原體的吞噬。臨床研究發(fā)現(xiàn)CR3與老年斑共存于AD患者腦內(nèi)，且AD患者小膠質(zhì)細(xì)胞CR3表達(dá)顯著上調(diào)[25]。CR3可通過與清道夫受體A的協(xié)同作用參與對(duì)Aβ的攝取和清除[26]。此外，CR3也參與Aβ刺激誘導(dǎo)的小膠質(zhì)細(xì)胞活化及隨后自由基的產(chǎn)生。

C5a是補(bǔ)體激活過程中產(chǎn)生的一種強(qiáng)促炎癥反應(yīng)分子。CD88是C5a的受體，主要表達(dá)在免疫細(xì)胞包括小膠質(zhì)細(xì)胞表面；CD88是一種趨化性受體，其功能與小膠質(zhì)細(xì)胞的聚集與活化有關(guān)，CD88的激活可導(dǎo)致炎癥細(xì)胞因子、活性氧、生物活性胺類及其它炎癥介質(zhì)的產(chǎn)生[27]。在AD模型小鼠，可觀察到Aβ斑塊附近的小膠質(zhì)細(xì)胞上CD88表達(dá)水平顯著上升[28]。此外，CD88拮抗劑可顯著性減少AD模型小鼠Aβ斑塊形成與膠質(zhì)細(xì)胞活化，同時(shí)改善場(chǎng)景記憶損傷[29]。

2.3 Fc受體(Fc receptors，F(xiàn)cRs)

FcRs與免疫球蛋白恒定域結(jié)合，不同免疫球白及其亞型均有相對(duì)應(yīng)的FcRs。小膠質(zhì)細(xì)胞可表達(dá)所有FcRs類型。主動(dòng)與被動(dòng)免疫研究表明，抗Aβ抗體可影響AD模型動(dòng)物Aβ清除及認(rèn)知功能減退[30-32]；在抗Aβ抗體存在條件下，小膠質(zhì)細(xì)胞中FcRs激活介導(dǎo)了對(duì)Aβ的吞噬作用[30,32]。然而也有研究發(fā)現(xiàn)，在抗Aβ抗體存在條件下Aβ的清除并不依賴于FcRs激活介導(dǎo)的吞噬作用[33]，表明除了FcRs介導(dǎo)的吞噬作用外還存在不依賴于FcRs的通路，該通路也介導(dǎo)了在抗Aβ抗體存在條件下對(duì)Aβ斑塊的清除作用[34]。臨床數(shù)據(jù)表明AD患者腦脊液中IgG水平明顯升高；有人認(rèn)為在AD病理狀態(tài)下血腦屏障功能受損進(jìn)而使得免疫球白進(jìn)入中樞引起后續(xù)反應(yīng)；也有人認(rèn)為可能存在血腦屏障內(nèi)的免疫球白合成途徑。因此，關(guān)于FcRs在AD發(fā)生發(fā)展中的作用及機(jī)制尚有待進(jìn)一步研究。

2.4 甲酰肽受體(Formyl peptide receptors，F(xiàn)PRs)

FPRs為七次跨膜、G蛋白偶聯(lián)受體，其功能主要是參與宿主防御病原體及某些內(nèi)源性分子。人類主要存在兩種FPRs，即FPR1與FPRL1；小鼠也表達(dá)兩種FPRs，即FPR1與FPR2。其中，F(xiàn)PRL1可與幾種宿主源性趨化激動(dòng)劑相互作用，包括HIV-1包膜蛋白，血清淀粉樣蛋白A和Aβ42[35-37]。在單核吞噬細(xì)胞，F(xiàn)PRL1和FPR2參與Aβ42誘導(dǎo)的IL-1β和超氧化物的分泌過程[35,38]。Aβ可誘導(dǎo)轉(zhuǎn)染FPRL1的HEK293細(xì)胞遷移和鈣動(dòng)員[35]；過表達(dá)FPRL1的HEK293細(xì)胞可內(nèi)吞Aβ42/FPRL1復(fù)合體入胞進(jìn)而導(dǎo)致胞內(nèi)Aβ42/FPRL1復(fù)合體的聚集[39]。進(jìn)一步實(shí)驗(yàn)結(jié)果表明，F(xiàn)PRL1與 FPR2均參與對(duì)Aβ42內(nèi)吞過程調(diào)節(jié)[39]。LPS處理不僅可刺激FPR2在小膠質(zhì)細(xì)胞的表達(dá)增加也可以引起小膠質(zhì)細(xì)胞的鈣動(dòng)員及對(duì)Aβ42的趨化反應(yīng)[40]。此外，干擾素處理也可增加小膠質(zhì)細(xì)胞FPR2表達(dá)水平及Aβ42誘導(dǎo)的細(xì)胞遷移[41]。上述結(jié)果表明，內(nèi)源或外源性因子可通過調(diào)節(jié)小膠質(zhì)細(xì)胞質(zhì)FPRs的表達(dá)進(jìn)而調(diào)制機(jī)體對(duì)Aβ的反應(yīng)，提示FPRs可能參與AD的病理進(jìn)程。

2.5 清道夫受體(Scavenger receptors,SRs)

SRs為細(xì)胞表面受體，主要參與細(xì)胞粘附和配體內(nèi)吞過程。中樞神經(jīng)系統(tǒng)中 SRs主要有兩類：SR-A與CD36；SR-A主要表達(dá)在小膠質(zhì)細(xì)胞和星形膠質(zhì)細(xì)胞，而CD36主要表達(dá)在小膠質(zhì)細(xì)胞和內(nèi)皮細(xì)胞上。已有的實(shí)驗(yàn)結(jié)果表明，SRs 可通過與Aβ結(jié)合促進(jìn)Aβ內(nèi)化引發(fā)炎癥反應(yīng)參與AD病理進(jìn)程[42]。

SR-A有三個(gè)亞型：SR-AI，SR AⅡ和SR AⅢ。SR-AI最初被描述為一個(gè)乙?；牡兔芏戎鞍资荏w；現(xiàn)在已經(jīng)知道，SR-AI可以與多種配體結(jié)合，如微生物配體、乙?；兔芏戎鞍?、內(nèi)毒素和Aβ等[43-45]。在AD患者腦組織老年斑附近的已激活的小膠質(zhì)細(xì)胞上可檢測(cè)到SR-AI 表達(dá)[44]。隨后證據(jù)顯示，SR-AI可通過與Aβ結(jié)合促進(jìn)Aβ內(nèi)化和清除[44,46-47]。

CD36是一種B型清道夫受體，存在包括小膠質(zhì)細(xì)胞在內(nèi)的多種類型的細(xì)胞中。已有的研究結(jié)果表明，CD36參與多種疾病的病理進(jìn)程如AD、動(dòng)脈粥樣硬化和瘧疾等。其中，CD36在AD病理進(jìn)程中的作用主要表現(xiàn)在CD36可以影響Aβ刺激誘導(dǎo)的小膠質(zhì)細(xì)胞聚集與激活過程[48- 49]。比如，在CD36受體缺陷小鼠中Aβ刺激誘導(dǎo)的小膠質(zhì)細(xì)胞中細(xì)胞因子和趨化因子表達(dá)顯著降低[49]。因此有人認(rèn)為抑制Aβ與CD36結(jié)合可能是阻斷Aβ誘導(dǎo)病理進(jìn)程的一個(gè)有效靶點(diǎn)。

2.6 晚期糖基化終產(chǎn)物受體(Receptor for advanced glycosylation endproducts，RAGE)

RAGE是免疫球蛋白超級(jí)家族成員受體，是一種多配體受體；除晚期糖基化終末產(chǎn)物外,RAGE還可以與多種配體結(jié)合如Aβ、神經(jīng)軸突生長(zhǎng)因子、S100蛋白、 淀粉p 肽以及甲狀腺素轉(zhuǎn)移酶等[50]。RAGE在內(nèi)皮細(xì)胞、巨噬細(xì)胞、平滑肌細(xì)胞和神經(jīng)元中均有表達(dá)；在中樞神經(jīng)系統(tǒng)，RAGE主要存在于神經(jīng)元、小膠質(zhì)細(xì)胞以及構(gòu)成血腦屏障的內(nèi)皮細(xì)胞上[51]。在AD 患者腦中,Aβ與RAGE 結(jié)合可促使小膠質(zhì)細(xì)胞向淀粉樣斑塊遷移并激活核因子kB (Nuclear factor kB NF-κB)繼而引起后續(xù)炎癥反應(yīng)[52]。RAGE與Aβ相互作用亦可激活蛋白激酶、c-Jun氨基末端激酶和ERK激酶[53]，這些信號(hào)通路的激活可促進(jìn)內(nèi)皮基質(zhì)金屬蛋白酶2的生成，而后者與血管炎癥反應(yīng)產(chǎn)生密切相關(guān)。進(jìn)一步實(shí)驗(yàn)證據(jù)表明，通過RAGE與Aβ相互作用誘導(dǎo)的小膠質(zhì)細(xì)胞活化涉及p38MAPK信號(hào)轉(zhuǎn)導(dǎo)途徑[54]。目前，正在發(fā)展以阻斷RAGE與Aβ相互作用為靶點(diǎn)的治療AD的小分子藥物。

3 小結(jié)與展望

AD發(fā)生發(fā)展的炎癥反應(yīng)機(jī)制是近年來(lái)的研究熱點(diǎn)。小膠質(zhì)細(xì)胞受體在Aβ與小膠質(zhì)細(xì)胞活化及后續(xù)炎癥反應(yīng)之間扮演了重要角色。本文列舉了幾種小膠質(zhì)細(xì)胞受體及其在AD發(fā)病中的作用，為AD的治療提供了新的思路。在今后研究中，需要進(jìn)一步詳細(xì)闡明小膠質(zhì)細(xì)胞受體介導(dǎo)AD病理進(jìn)程的分子機(jī)制及不同受體間的相互作用，為設(shè)計(jì)新的靶向藥物提供理論依據(jù)。

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10.15972/j.cnki.43-1509/r.2015.01.026

2014-09-06；

2014-10-20

*通訊作者，E-mail:652797262@qq.com.

R741

A

(此文編輯：蔣湘蓮)