晚期糖基化終末產(chǎn)物與阿爾茨海默病的關(guān)系

馬宗艷，蔡宏斌，葛朝明

認(rèn)知障礙在中老年人中高發(fā)，常見的認(rèn)知障礙主要有輕度認(rèn)知障礙和癡呆[1]。據(jù)2015年全球癡呆報(bào)告，平均每3s即有新診斷為癡呆的患者1例，其中年齡大于60歲的老年癡呆患者約4850萬(wàn)，而老年癡呆的主要原因包括阿爾茨海默病(Alzheimer's disease，AD)、血管性癡呆(vascular dementia，VD)、路易體癡呆(dementia with Lewy bodies，DLB)和額顳葉癡呆(frontotemporal dementia，F(xiàn)TD)等，其中最常見的為AD，約占全部癡呆患者的60%[2-4]。越來(lái)越多的研究關(guān)注到晚期糖基化終末產(chǎn)物(advanced glycation end products，AGEs)與認(rèn)知功能障礙的關(guān)系，并認(rèn)為AGEs可能也是引起AD的原因之一[5]。

1 晚期糖基化終末產(chǎn)物(advanced glycation end products，AGEs)及其受體(RAGE)的概述

1.1 AGEs的化學(xué)結(jié)構(gòu)及特征 AGEs是蛋白質(zhì)、脂質(zhì)、核酸等大分子的游離氨基與葡萄糖或其他還原糖的羰基經(jīng)非酶催化反應(yīng)生成的穩(wěn)定的終末產(chǎn)物[6]，反應(yīng)早期生成不穩(wěn)定的Schiff堿，當(dāng)葡萄糖濃度下降時(shí)，Schiff堿即可發(fā)生逆轉(zhuǎn)，通過(guò)結(jié)構(gòu)重排形成比較穩(wěn)定的酮胺化合物，成為早期糖基化產(chǎn)物，經(jīng)過(guò)復(fù)雜的脫水、氧化、縮合等過(guò)程，形成穩(wěn)定、不可逆的AGEs[7]。AGEs根據(jù)其結(jié)構(gòu)和生成途徑的不同可分為兩種：一種類似于咪唑衍生物，如戊糖苷素(pentosidine)、羧乙基賴氨酸(Nε-carboxyethyllysine，CEL)等；另一種如羧甲基賴氨酸(Nε-carboxymethyllysine，CML)、吡咯素(pyrraline)等[8]。AGEs的主要分子結(jié)構(gòu)類型有吡咯醛、羧甲基絲氨酸、苯妥西定、咪唑酮以及一些交聯(lián)產(chǎn)物[9]。AGEs的共同特征如下：呈棕色，有特殊的吸收光譜及熒光特性；與氨基酸基團(tuán)之間有物理性交聯(lián)特性；與氧化修飾有關(guān)；對(duì)酶穩(wěn)定，不易降解；可與許多細(xì)胞膜特異性受體結(jié)合發(fā)揮生物學(xué)效應(yīng)等[9]。在正常情況下，AGEs修飾蛋白作為一種信號(hào)參與機(jī)體清除衰老組織及結(jié)構(gòu)重建的過(guò)程，病理狀態(tài)下，AGEs可引起組織的細(xì)胞結(jié)構(gòu)和功能異常，從而產(chǎn)生一系列病理變化，在年齡相關(guān)的退行性病變?nèi)鏏D、動(dòng)脈粥樣硬化性疾病、帕金森病中均有重要作用[10]。

1.2 AGEs在AD患者大腦內(nèi)的分布 Horie等[11]研究發(fā)現(xiàn)，AD患者大腦海馬區(qū)和海馬旁區(qū)的神經(jīng)細(xì)胞核周體和神經(jīng)細(xì)胞核周體外沉積的脂褐素中，以及神經(jīng)纖維網(wǎng)的纖維樣結(jié)構(gòu)和老年斑中存在AGEs結(jié)構(gòu)；他們的免疫組化研究還發(fā)現(xiàn)，AD患者大腦內(nèi)老年斑和神經(jīng)元纖維纏結(jié)(neurofibrillary tangles，NFTs)中均有AGEs聚積，修飾大腦內(nèi)的NFTs和Tau蛋白。同時(shí)，與AD病理改變有關(guān)的異常結(jié)構(gòu)成分如極低密度脂蛋白(very low-density lipoprotein，VLDL)、C反應(yīng)蛋白(C-reactive protein，CRP)、載脂蛋白E(apolipoprotein E，ApoE)均存在糖基化現(xiàn)象[12]；體外實(shí)驗(yàn)證實(shí)，神經(jīng)元中也存在AGEs[13]，提示中樞神經(jīng)系統(tǒng)中AGEs 蓄積與AD患者神經(jīng)元的變性死亡有關(guān)。

1.3 AGEs受體RAGE的化學(xué)結(jié)構(gòu)及特性 RAGE是一組完整的膜蛋白，由400 多個(gè)氨基酸組成，分別由較大的細(xì)胞外段、跨膜段及短的細(xì)胞內(nèi)段3個(gè)部分構(gòu)成[14]。其細(xì)胞外域含3個(gè)免疫球蛋白樣區(qū)域：一個(gè)V型結(jié)構(gòu)域和緊連的兩個(gè)C型結(jié)構(gòu)域(C1/C2)，V結(jié)構(gòu)域?yàn)榕潴w結(jié)合區(qū)域[15]?？扇苄訰AGE (soluble RAGE，sRAGE) 即RAGE 細(xì)胞外段，為配體結(jié)合部位，具有V型片段緊接著兩個(gè)C型片段的免疫球蛋白樣結(jié)構(gòu)[14]。RAGE在正常人的肺、腎等器官中也存在，但表達(dá)低下，在阿爾茨海默病、糖尿病、透析相關(guān)性腎病、動(dòng)脈粥樣硬化及多種腫瘤等疾病狀態(tài)下表達(dá)明顯升高[16]。RAGE配體主要包括AGEs、β-淀粉樣肽(β-amyloid，Aβ)、高遷移率族蛋白B1(high mobility group box 1，HMGB1)，S100/鈣粒蛋白等[17]。

2 AGEs與AD發(fā)生發(fā)展的關(guān)系

2.1 AGEs與Aβ和Tau蛋白的關(guān)系 大量研究表明，AD的病理學(xué)特征主要包括神經(jīng)元內(nèi)的NETs和神經(jīng)元外的老年斑形成，NETs則主要由過(guò)度磷酸化的Tau蛋白構(gòu)成，而老年斑主要由Aβ聚集而成[18-19]。通過(guò)免疫組織化學(xué)研究也發(fā)現(xiàn)AGEs與AD的兩大病理特征為NETs與老年斑的共定位[20]。AGEs的修飾可以延長(zhǎng)Aβ的半衰期，導(dǎo)致可溶性Aβ變成不溶性的纖維樣聚合體而沉積，AGEs再通過(guò)交聯(lián)作用促使更多的Aβ生成淀粉樣纖維不斷沉積，從而形成惡性循環(huán)；同時(shí)，Aβ可激活小膠質(zhì)細(xì)胞，誘導(dǎo)前炎癥因子白細(xì)胞介素-1β(interleukin-1β，IL-1β)和轉(zhuǎn)化生長(zhǎng)因子-α(transforming growth factor-α，TGF-α)的釋放，誘發(fā)AD早期的炎癥反應(yīng)，而糖基化的Aβ可以通過(guò)上調(diào)RAGE和糖原合成酶激酶-3(glycogen synthase kinase，GSK-3)的表達(dá)加劇神經(jīng)毒性[21]。

外源性AGEs可誘導(dǎo)體內(nèi)、體外Tau蛋白多個(gè)位點(diǎn)的過(guò)度磷酸化，伴隨有RAGE的激活、蛋白激酶B(protein kinase B，PKB/Akt)的抑制、p38激活、GSK-3激活和細(xì)胞外調(diào)節(jié)蛋白激酶(ERK1/2)的激活，并且通過(guò)抑制興奮性突觸后電位的長(zhǎng)時(shí)程增強(qiáng)(long-term potentiation，LTP)、減少樹突棘數(shù)目以及降低突觸蛋白水平，從而影響空間記憶功能[21]；過(guò)度磷酸化的Tau蛋白與微管的結(jié)合能力降低，喪失了促進(jìn)微管裝配的功能，引起微管解聚，降低軸突的轉(zhuǎn)運(yùn)效率，損害突觸功能，導(dǎo)致神經(jīng)損傷和認(rèn)知功能障礙[22]。

2.2 AGEs與細(xì)胞代謝的關(guān)系 AGEs激活RAGE，上調(diào)細(xì)胞內(nèi)的活性氧基團(tuán)(reactive oxygen species，ROS)水平，使煙酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶的活性增加，有助于增強(qiáng)Ras相關(guān)的C3肉毒素底物1(Ras-related C3botulinum toxin substrate 1，Rac1)的表達(dá)，從而促進(jìn)細(xì)胞凋亡、抑制細(xì)胞增殖。同時(shí)，AGEs可以通過(guò)刺激內(nèi)皮祖細(xì)胞上的RAGE受體，激活c-Jun氨基末端激酶(c-jun-N-terminal kinase，JNK)信號(hào)通路，與AGEs相互作用誘導(dǎo)細(xì)胞凋亡[23]。Chen等[24]研究發(fā)現(xiàn)，抑制RAGE和氧化應(yīng)激能明顯降低AGEs誘導(dǎo)的細(xì)胞損傷，使凋亡相關(guān)因子caspase-3，caspase-9等表達(dá)明顯降低。Ko等[25]在神經(jīng)母細(xì)胞瘤細(xì)胞中發(fā)現(xiàn)AGEs誘導(dǎo)ROS生成增加，上調(diào)葡萄糖調(diào)節(jié)蛋白78(glucose-regulated protein 78，GRP78)表達(dá)，啟動(dòng)內(nèi)質(zhì)網(wǎng)應(yīng)激，導(dǎo)致細(xì)胞凋亡增加。也有研究發(fā)現(xiàn)細(xì)胞內(nèi)的AGEs可使細(xì)胞骨架蛋白發(fā)生交聯(lián)，通過(guò)干擾軸突運(yùn)輸和蛋白裝配干擾細(xì)胞功能，引起細(xì)胞損傷和凋亡[26]。還有研究表明，AGEs可通過(guò)自身的直接細(xì)胞毒性，特異性抑制功能性蛋白，促進(jìn)蛋白交聯(lián)、聚集，產(chǎn)生ROS，使蛋白質(zhì)、脂質(zhì)、核酸發(fā)生非酶糖基化，引起結(jié)構(gòu)和功能的改變，導(dǎo)致微血管的通透性增高[27]，促進(jìn)神經(jīng)元細(xì)胞凋亡，Takeuchi等[28]發(fā)現(xiàn)AGEs可致BHK21倉(cāng)鼠成纖維細(xì)胞、人神經(jīng)母細(xì)胞瘤細(xì)胞、原代星型膠質(zhì)細(xì)胞、單核細(xì)胞和鼠小膠質(zhì)細(xì)胞死亡。

2.3 AGEs與神經(jīng)元的關(guān)系 研究表明 ，在AD患者中，細(xì)胞周期相關(guān)基因可在不同的神經(jīng)元中共表達(dá)，這可能與異常的有絲分裂信號(hào)有關(guān)。小膠質(zhì)細(xì)胞和星形膠質(zhì)細(xì)胞在淀粉樣斑塊附近增生，由斑塊活化的神經(jīng)膠質(zhì)細(xì)胞可分泌斑塊成分或細(xì)胞因子，從而誘導(dǎo)神經(jīng)元發(fā)出有絲分裂信號(hào)[13]。

AGEs可能是這些有絲分裂的化合物之一，在原代神經(jīng)元細(xì)胞中AGEs可激活P42/44絲裂原活化蛋白激酶(MAPK)級(jí)聯(lián)通路，刺激靜息神經(jīng)元重新進(jìn)入S/G2期，促進(jìn)AD患者的神經(jīng)變性過(guò)程[13]；在AD患者的大腦中可見大量AGEs顆粒陽(yáng)性的神經(jīng)元，多沉積于多倍體神經(jīng)元附近；錐體細(xì)胞胞質(zhì)內(nèi)也有較強(qiáng)的AGEs免疫反應(yīng)，AGEs通過(guò)MAPK級(jí)聯(lián)啟動(dòng)有絲分裂信號(hào)，可能是觸發(fā)神經(jīng)元從細(xì)胞周期G0過(guò)渡到G1期的一個(gè)潛在因素[13]。

2.4 AGEs與線粒體功能障礙的關(guān)系 線粒體功能障礙可能是導(dǎo)致AGEs所致的神經(jīng)細(xì)胞病變的一個(gè)重要原因。有研究表明，用AGEs處理的細(xì)胞會(huì)失去線粒體功能的完整性，產(chǎn)生的ROS導(dǎo)致線粒體膜電位的破壞，使線粒體通透性發(fā)生變化，細(xì)胞同時(shí)還釋放細(xì)胞色素C，促進(jìn)caspase-3的表達(dá)，誘導(dǎo)細(xì)胞凋亡[29]。AGEs-RAGE還能導(dǎo)致能量代謝障礙和線粒體功能障礙，從而影響認(rèn)知功能[30]。線粒體呼吸鏈通過(guò)激活RAGE誘導(dǎo)ROS的產(chǎn)生，這使得AGEs處理的內(nèi)皮細(xì)胞上血管細(xì)胞黏附分子-1(vascular cell adhesion molecule-1，VCAM-1)表達(dá)上調(diào)和增加[31]。RAGE可以作為一種神經(jīng)元細(xì)胞表面的載體，依賴p38絲裂原激活蛋白激酶(p38MAPK)信號(hào)途徑而發(fā)生活化，導(dǎo)致細(xì)胞線粒體功能障礙、氧化應(yīng)激，最終發(fā)生神經(jīng)損傷[32]。

2.5 AGEs與氧化應(yīng)激的關(guān)系 越來(lái)越多的研究表明，氧化應(yīng)激在AD的發(fā)病機(jī)制中有非常重要的作用。AGEs與RAGE結(jié)合導(dǎo)致ROS生成增加，攻擊細(xì)胞膜脂質(zhì)、DNA和蛋白質(zhì)，產(chǎn)生氧化應(yīng)激損傷，而升高的細(xì)胞間ROS水平反過(guò)來(lái)又進(jìn)一步刺激AGEs的不斷生成，形成“氧化應(yīng)激-AGEs”的惡性循環(huán)[33]。Hayashi等[33]研究表明，氧化應(yīng)激引起內(nèi)質(zhì)網(wǎng)功能紊亂，在缺血性神經(jīng)細(xì)胞損傷中發(fā)揮著重要作用。也有研究表明，AGEs生成過(guò)程中的氧自由基生成增加，機(jī)體抗氧化能力下降，過(guò)量的氧自由基通過(guò)攻擊細(xì)胞膜脂質(zhì)、蛋白質(zhì)和DNA造成組織細(xì)胞損傷[34]。

2.6 AGEs與自噬的關(guān)系 自噬是一種高度保守的分解代謝過(guò)程，可以調(diào)節(jié)真核細(xì)胞能量平衡[35]，而過(guò)度自噬可能導(dǎo)致細(xì)胞損傷[36]。研究表明，AGEs前體二羰基化合物可與蛋白質(zhì)、脂類和核酸直接反應(yīng)，修改其結(jié)構(gòu)并影響其組織微環(huán)境，它們還可以誘導(dǎo)ROS升高，增強(qiáng)細(xì)胞的氧化應(yīng)激反應(yīng)，AGEs-RAGE信號(hào)通路的激活則會(huì)介導(dǎo)炎癥、氧化應(yīng)激、自噬和細(xì)胞凋亡，導(dǎo)致基因組不穩(wěn)定和癌癥發(fā)生[37]。另有研究表明，AGEs可通過(guò)PI3K/AKT/mTOR和ERK信號(hào)通路誘導(dǎo)自噬過(guò)程[38]。

2.7 AGEs與血腦屏障(BBB)的關(guān)系 BBB通過(guò)特定的運(yùn)輸系統(tǒng)為大腦提供營(yíng)養(yǎng)，同時(shí)促進(jìn)代謝產(chǎn)物的排除，保護(hù)大腦，避免有害物質(zhì)導(dǎo)致的損害[39]。糖基化使內(nèi)皮細(xì)胞和(或)底層基質(zhì)蛋白內(nèi)皮細(xì)胞的屏障功能下降；同時(shí)糖基化會(huì)導(dǎo)致RAGE的表達(dá)上調(diào)，而使緊密連接蛋白(zonula occludens-1，ZO-1)的表達(dá)下降，促進(jìn)白細(xì)胞介素6(interleukin-6，IL-6)和白細(xì)胞介素8(interleukin-8，IL-8)等炎癥介質(zhì)分泌，從而影響B(tài)BB的通透性[40]。

2.8 AGEs與炎癥反應(yīng)的關(guān)系 研究表明，AGEs水平升高可刺激細(xì)胞因子或趨化因子的分泌。AGEs通過(guò)AGEs-RAGE信號(hào)軸，導(dǎo)致ROS生成增加，誘導(dǎo)活化轉(zhuǎn)錄因子，如核轉(zhuǎn)錄因子κB(NF-κB)、信號(hào)轉(zhuǎn)導(dǎo)子及轉(zhuǎn)錄因子活化子STAT3(signal transducer and activation of transcription 3，STAT3)、缺氧誘導(dǎo)因子-1α(hypoxia inducible factor-1α，HIF-1α)等的產(chǎn)生，增加細(xì)胞因子(如IL-1β、IL-6)的分泌，促進(jìn)細(xì)胞間黏附分子-1(intercelular adhesion molecule-1，ICAM-1)、內(nèi)皮素 -1(endothelin-1，ET-1)生成，使內(nèi)皮型一氧化氮合酶(endothelial nitric oxide synthases，eNOS)的表達(dá)降低，而前述過(guò)程貫穿AD病變的始終[41]。研究表明AGEs可以濃度依賴的方式增加巨噬細(xì)胞脂質(zhì)積累，升高巨噬細(xì)胞膽固醇酯的水平，降低高密度脂蛋白(highdensity lipoprotein，HDL)介導(dǎo)的膽固醇流出，并通過(guò)激活過(guò)氧化物酶體增殖物活化受體γ(peroxisome proliferators-activated receptor gamma，PPARγ)和NF-κB信號(hào)通路導(dǎo)致ROS和活性氮(reactive nitrogen species，RNS)的產(chǎn)生，從而引發(fā)一系列炎癥反應(yīng)[42]。

3 AGEs與認(rèn)知障礙預(yù)后的關(guān)系

AGEs可以通過(guò)多種途徑促進(jìn)AD的發(fā)生和發(fā)展，阻斷AGEs及其受體RAGE的作用途徑，有望成為治療的新靶點(diǎn)，對(duì)認(rèn)知障礙的防治具有重要的實(shí)際意義。

3.1 阻斷AGEs作用途徑 AGEs抑制劑通過(guò)減少Aβ的聚集及毒性，改變AGEs的結(jié)構(gòu)，從而抑制AGE與其受體結(jié)合，通過(guò)多種保護(hù)性作用機(jī)制而發(fā)揮治療AD的作用。AGEs抑制劑氨基胍可減少AGEs介導(dǎo)的糖尿病血管并發(fā)癥的發(fā)生；替尼西坦可與糖和糖基化蛋白反應(yīng)，在離體條件下抑制AGEs導(dǎo)致的氨基酸和蛋白質(zhì)交聯(lián)，作為改善認(rèn)知的抗癡呆藥[43]。Ishibashi等[44]的研究表明，諾麗果正丁醇提取物可以抑制AGEs的有害影響，打破RAGE在內(nèi)皮細(xì)胞表達(dá)與ROS產(chǎn)生之間的惡性循環(huán)；也有研究表明西地那非能保護(hù)線粒體免受AGEs引起的損傷，阻止由于線粒體功能障礙途徑和線粒體膜電位降低等原因所致的細(xì)胞凋亡，從而改善AD患者的認(rèn)知功能障礙[29]。

3.2 阻斷AGEs-RAGE通路作用途徑 大量研究表明，通過(guò)阻斷AGEs-RAGE軸可改善認(rèn)知障礙[45-49]。Liu等[45]研究發(fā)現(xiàn)，過(guò)表達(dá)肌動(dòng)蛋白解聚因子(actin depolymerizing factor，ADF)可抑制AGEs誘導(dǎo)的蛋白質(zhì)表達(dá)，上調(diào)RAGE并減少ROS的形成，表明ADF可通過(guò)與AGEs相互作用改善認(rèn)知障礙。Chen等[46]研究證實(shí)法舒地爾和FPS-ZM1(一種RAGE特異性抑制劑)通過(guò)抑制AGEs/RAGE/Rho/ROCK通路，延緩AD的進(jìn)展。Hong等[47]研究發(fā)現(xiàn)， FPS-ZM1可以阻斷RAGE的產(chǎn)生和AGEs-RAGE介導(dǎo)的氧化應(yīng)激，增強(qiáng)腦組織的抗氧化能力，降低AGEs誘導(dǎo)的神經(jīng)損傷，從而改善認(rèn)知功能，所以有望成為AD的防治藥物。Piperi等[48]研究發(fā)現(xiàn)激活胰高血糖素樣肽-1(glucagon-like peptide-1，GLP-1)受體可抑制NADPH氧化酶的活性，并通過(guò)抑制NF-κB下調(diào)RAGE的表達(dá)，降低ROS生成，可能對(duì)糖尿病相關(guān)的AD有治療價(jià)值。Matsui等[49]研究表明蘿卜硫素通過(guò)抑制AGEs-RAGE軸，減少AGEs誘導(dǎo)的內(nèi)皮細(xì)胞炎癥反應(yīng)。

3.3 生活方式干預(yù) 在機(jī)體內(nèi)，飲食是AGEs親氧化和促炎反應(yīng)的一個(gè)主要環(huán)境來(lái)源，最近研究表明，來(lái)自高脂肪和干熱加工食品的AGEs消費(fèi)增加，可增加糖尿病患者和肥胖者大腦中AGEs的積累[50]。食品和吸煙衍生的AGEs也被證明在許多與衰老有關(guān)的疾病中發(fā)揮病理作用，減少食物中的AGEs水平，限制AGEs豐富的飲食，在食品的加工、貯藏和運(yùn)輸?shù)冗^(guò)程中可通過(guò)選擇性的縮短加工食品的時(shí)間、降低加工溫度、降低食品pH，阻止飲食中AGEs的吸收可能，這些措施可能是減緩老化過(guò)程的一種新的治療策略，有可能減少或阻止AD的破壞性癥狀的發(fā)生[51]。有研究表明，果糖和其代謝產(chǎn)物的高反應(yīng)性可能有助于促進(jìn)細(xì)胞內(nèi)AGEs的形成和血管并發(fā)癥的發(fā)生，減少果糖的攝入及拮抗果糖在體內(nèi)的作用可能改善認(rèn)知障礙[52]。

4 總結(jié)與展望

研究表明，血清AGEs和sRAGE水平可以作為認(rèn)知障礙患者的血清標(biāo)志物，預(yù)測(cè)2型糖尿病患者早期認(rèn)知功能下降[53]；而Reynaert等[54]的研究表明，AGEs或sRAGE不太可能作為疾病的生物標(biāo)志物，仍需更多的研究明確其應(yīng)用價(jià)值。通過(guò)AGEs及其受體RAGE途徑改善認(rèn)知障礙的研究多為實(shí)驗(yàn)研究，人體試驗(yàn)相對(duì)較少，TTP488(也被稱為Azeliragon，一種選擇性RAGE小分子抑制劑)應(yīng)用于AD患者試驗(yàn)，因其不良反應(yīng)導(dǎo)致試驗(yàn)終止，新的、安全有效藥物臨床應(yīng)用尚有待探索[55-56]。既往研究表明，AGEs受體RAGE的GLy82Ser基因多態(tài)性可導(dǎo)致sRAGE水平下降，在AD和糖尿病微循環(huán)并發(fā)癥的發(fā)生發(fā)展中起著重要作用[57]，但相關(guān)研究仍較少，需要進(jìn)一步證實(shí)。大量動(dòng)物實(shí)驗(yàn)表明，中醫(yī)尤其是中藥通過(guò)AGEs/RAGE途徑治療認(rèn)知障礙有很大前景，但其臨床應(yīng)用尚待進(jìn)一步探索。臨床流行病學(xué)研究顯示，AD和VD共享血管危險(xiǎn)因素，但其共同發(fā)病機(jī)制仍不清楚[52,58]，AGEs及其受體在AD和VD的共同作用機(jī)制仍須進(jìn)一步探索。

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