朱紅梅 張鳳蘭 肖志成,2* 陳芳.昆明醫(yī)科大學(xué)分子臨床醫(yī)學(xué)研究院，云南省干細胞和再生醫(yī)學(xué)重點實驗室, 云南 昆明 650500；2.莫納什大學(xué)免疫與干細胞實驗室，澳大利亞 墨爾本 3800;3.昆明醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院，云南 昆明 650500

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淀粉樣前體蛋白在神經(jīng)發(fā)生中的作用與阿爾茨海默病關(guān)系的研究進展

朱紅梅1張鳳蘭1肖志成1,2*陳芳3*
1.昆明醫(yī)科大學(xué)分子臨床醫(yī)學(xué)研究院，云南省干細胞和再生醫(yī)學(xué)重點實驗室, 云南 昆明 650500；2.莫納什大學(xué)免疫與干細胞實驗室，澳大利亞 墨爾本 3800;3.昆明醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院，云南 昆明 650500

阿爾茨海默病，俗稱老年癡呆，由德國外科醫(yī)生Alzheimer首次發(fā)現(xiàn)，是一種進行性發(fā)展、致死性神經(jīng)系統(tǒng)退行性疾病。該病是目前最常見的一種失智癥(俗稱癡呆癥，Dementia)，但這種失智不同于正常老化。迄今為止AD具體的發(fā)病機制仍未明確、也沒有精準(zhǔn)的早期篩查和診斷手段及有效控制病情的治療方法。近年來大量研究證實成年哺乳動物的中樞神經(jīng)系統(tǒng)終身存在著神經(jīng)發(fā)生。這為腦損傷和神經(jīng)系統(tǒng)變性疾病的治療帶來了希望。文章將對成年中樞神經(jīng)系統(tǒng)神經(jīng)發(fā)生的過程及參與AD病程的關(guān)鍵分子APP在神經(jīng)發(fā)生方面的最新發(fā)現(xiàn)進行綜述，以期為本領(lǐng)域或相關(guān)研究提供借鑒或參考。

淀粉樣前體蛋白; 神經(jīng)發(fā)生；阿爾茨海默病

阿爾茨海默病(Alzheimer disease，AD) 是發(fā)生于老年及老年前期最常見的，以進行性癡呆為特征的中樞神經(jīng)系統(tǒng)退行性疾病。該病以近期記憶障礙、認知功能障礙、語言障礙及人格異常等神經(jīng)精神癥狀為顯著臨床表現(xiàn)[1]，發(fā)病隱匿，呈不可逆的進行性進展表現(xiàn)，病程可長達20～30年，最后呈嚴重癡呆以至植物人狀態(tài)。隨著人類壽命的延長及人口老齡化，AD對人類健康的危害日益突出，是僅次于心血管病、癌癥、腦卒中之后嚴重威脅老年人生命健康的高發(fā)病，已成為當(dāng)前老年醫(yī)學(xué)面臨的最為嚴峻的醫(yī)學(xué)問題之一[2-3]。然而，自1906發(fā)現(xiàn)該病至今，其發(fā)病機制仍未完全明確，也無精準(zhǔn)的早期診斷手段及有效的治療方法。神經(jīng)干細胞(neural stem cells， NSCs)在一定的條件下可增殖分化為神經(jīng)元和神經(jīng)膠質(zhì)細胞，進而整合到現(xiàn)有的神經(jīng)回路中，參與神經(jīng)功能的維持及修復(fù)等過程，此稱之為神經(jīng)發(fā)生。傳統(tǒng)觀念認為，神經(jīng)發(fā)生主要存在于胚胎發(fā)育期，成年哺乳動物中無神經(jīng)發(fā)生。近年來大量研究證實成年哺乳動物的中樞神經(jīng)系統(tǒng)終身存在著神經(jīng)發(fā)生，這為腦損傷及AD等發(fā)病機制的研究開辟了新思路。對成體大腦神經(jīng)發(fā)生的研究將對臨床腦損傷的修復(fù)及AD等疾病的治療具有重要意義[4-6]。此外，近年來研究發(fā)現(xiàn)AD發(fā)生發(fā)展相關(guān)的關(guān)鍵分子和信號通路同時影響了神經(jīng)發(fā)生，并有研究證實海馬神經(jīng)發(fā)生的改變要早于AD的特征性損傷[7-10]。由于在AD的病程中，海馬是最易受損的區(qū)域之一，該部位的AD病理變化表現(xiàn)得較為明顯，且該腦區(qū)的受損往往導(dǎo)致了AD的最早期癥狀、學(xué)習(xí)記憶缺陷的出現(xiàn)。因此，研究神經(jīng)發(fā)生，尤其是海馬神經(jīng)發(fā)生的變化及機制，已成為當(dāng)前AD病理機制研究的一個新的浪潮。由于AD患者普遍存在β淀粉樣蛋白(beta-Amyloid protein，Aβ)的高表達，而APP是導(dǎo)致Aβ生成的關(guān)鍵分子。APP及其水解產(chǎn)物在AD的病理過程中扮演著重要的作用且能影響神經(jīng)發(fā)生。本文主要介紹中樞神經(jīng)系統(tǒng)神經(jīng)發(fā)生的過程及參與AD病程的關(guān)鍵分子APP在成體神經(jīng)發(fā)生中的作用，從而進一步明確APP在成體神經(jīng)發(fā)生中的作用與AD發(fā)病的聯(lián)系，以期為AD發(fā)病機制的研究提供思路和參考。

1 APP與AD的關(guān)系

近年來諸多研究表明，AD是一種多病因參與的復(fù)雜疾病。該病主要包括兩種類型，家族性阿爾茨海默病(FAD)和散發(fā)性阿爾茨海默病(SAD)，臨床上較為常見的是SAD。目前有研究認為，F(xiàn)AD主要由PS1、PS2和APP基因突變所致[11-13]；而SAD的發(fā)病機制較為復(fù)雜，是多因素共同作用的結(jié)果。但這兩種類型疾病的進展和病理變化基本相同，其主要的病理改變包括β淀粉樣蛋白沉積引起的老年斑(senile plaque, SP)，細胞骨架蛋白Tau蛋白過度磷酸化引起的神經(jīng)元內(nèi)神經(jīng)元纖維纏結(jié)(neurofibrillary tangle, NFT)及大面積的神經(jīng)元死亡[14-15]。大量研究證明β淀粉樣蛋白(beta-Amyloid protein，Aβ)在AD發(fā)病中，起重要病理作用，是SP的核心成分[14-15]。其在體內(nèi)存在著多種形態(tài)：包括可溶性的游離態(tài)、寡聚態(tài)及中間態(tài)的初原纖維(protofibrils)及不溶性的原纖維(fibrils)。后者易沉積形成SP。但寡聚態(tài)的Aβ被認為具有更強的毒性，是AD的主要病因，此為AD發(fā)病的“Aβ假說”，該假說是目前已被廣泛接受的AD的主要致病機理。而淀粉樣前體蛋白(amyloid precursor protein，APP)是Aβ的前體蛋白,這說明Aβ聚集所產(chǎn)生的神經(jīng)毒性，需要APP的酶解加工過程的參與。此外，APP基因敲除小鼠在小鼠發(fā)育、突觸功能、學(xué)習(xí)記憶等方面表現(xiàn)異常[16-20]。可見，APP蛋白在生理過程中扮演了諸多重要的角色，其基因結(jié)構(gòu)及功能的異?？赡芘cAD的發(fā)病密切相關(guān)。

2 APP的主要結(jié)構(gòu)及裂解過程

APP是一種廣泛存在于全身組織細胞上的單次跨膜蛋白，由多個功能區(qū)組成，包括大的N-末端胞外結(jié)構(gòu)域、跨膜區(qū)(即Aβ區(qū))及小的C-末端胞漿區(qū)。其中胞外區(qū)是一個較復(fù)雜的結(jié)構(gòu)，由幾個獨立的結(jié)構(gòu)域組成，具有相對獨立的功能。據(jù)最新文獻報道，APP可被α、β、γ和η分泌酶切割形成不同的肽段[21-26]。并在這些分泌酶的作用下以3種不同的途徑裂解(見圖1)：①非淀粉樣途徑：為APP的主要裂解途徑，裂解位點在Aβ序列間，裂解酶為α分泌酶(和γ分泌酶)。APP先經(jīng)α分泌酶在α位剪切，在APP的N端產(chǎn)生可溶性的APP片段(sAPPα)，在C端產(chǎn)生CTFα片段，CTFα再經(jīng)γ分泌酶剪切產(chǎn)生P3及胞漿內(nèi)片段AICD，此途徑不形成Aβ。②淀粉樣途徑：為APP的次要裂解途徑，裂解位點在Aβ序列兩側(cè)，裂解酶為β和γ分泌酶。此途徑APP先經(jīng)β分泌酶剪切，可在N端產(chǎn)生sAPPβ片段，在C端產(chǎn)生CTFβ片段，CTFβ再經(jīng)γ分泌酶剪切就會產(chǎn)生全長的Aβ[21,27]。其中含有42個氨基酸的Aβ42具有較強的神經(jīng)毒性，且最易聚集和沉積，最終形成老年斑，可導(dǎo)致神經(jīng)元退行性變和癡呆[28-29]。③η分泌酶途徑：存在多個裂解位點，但此途徑不生成Aβ。其中，前兩個途徑為APP的經(jīng)典裂解途徑，在病理狀態(tài)下，APP的次要裂解途徑(Aβ途徑)發(fā)揮著主要作用。

對APP裂解的調(diào)節(jié)，是生理和病理過程的一個關(guān)鍵事件。然而，APP的各種裂解產(chǎn)物的病理生理意義尚未研究清楚，可能與APP的定位、翻譯后修飾及寡聚化狀態(tài)相關(guān)[29-34]。

3 成體神經(jīng)發(fā)生

據(jù)大量文獻報道，NSCs不僅存在于發(fā)育中的哺乳動物神經(jīng)系統(tǒng)，而且還存在于成年動物腦內(nèi)[35-38]。成體腦中的NSCs通過分裂、增殖后產(chǎn)生神經(jīng)前體細胞(neural precursor cells,NPCs)，它們經(jīng)過遷移、分化形成成熟的神經(jīng)元，進而整合入神經(jīng)網(wǎng)絡(luò)發(fā)揮作用，這一系列過程稱為(成體)神經(jīng)發(fā)生(neurogenesis)。在成年哺乳類動物大腦中主要有2個區(qū)域存在持續(xù)的神經(jīng)發(fā)生：腦室室管膜下區(qū)(subventricular zone，SVZ)和海馬齒狀回顆粒下區(qū)(subgranular zone of the dentate gyrus in the hippocampus，SGZ)，以維持嗅球及海馬神經(jīng)元的更新。神經(jīng)發(fā)生的程度與這兩個成體神經(jīng)發(fā)生的關(guān)鍵腦區(qū)神經(jīng)前體細胞的遷移和分化及新生神經(jīng)元的存活密切相關(guān)。

圖1 APP裂解途徑(引自參考文獻[24])

4 APP在神經(jīng)發(fā)生中的作用

大量研究表明APP的裂解產(chǎn)物對神經(jīng)干細胞的增殖和分化具有重要的調(diào)控作用。筆者對研究報道較多的sAPPα、AICD及Aβ共3個主要的裂解產(chǎn)物在神經(jīng)發(fā)生中的作用進行闡述。

4.1 sAPPα正向調(diào)控神經(jīng)發(fā)生 早期有文獻指出，從胎鼠腦組織中分離SVZ源性的NPCs，sAPPα可促進其增殖[39]。有研究認為，sAPPα促NPC增殖可能與其結(jié)構(gòu)與生長因子類似有關(guān)[40]。2004年，Caille等[41]首次報道sAPPα對成體神經(jīng)發(fā)生有作用：將sAPPα注射入小鼠側(cè)腦室，可觀察到NPC的數(shù)量增多；相反地，用α分泌酶抑制劑阻斷sAPPα的生成或用APP的反義寡核苷酸下調(diào)APP的生成，均導(dǎo)致NPC的數(shù)量減少。這說明，sAPPα能促進NPCs增殖。他們還探討了其促增殖的作用可能與SVZ區(qū)的A細胞的增殖有關(guān)?？梢?，sAPPα可促進胚胎和成體的SVZ源性的NPC增殖。最新的報道指出，sAPPα在體外實驗中，可促進另一成體發(fā)生系統(tǒng)—SGZ區(qū)的NPC的增殖，并促進細胞存活[42]。向衰老C57BL/6小鼠(20個月)的腦室單次注射sAPPα可逆轉(zhuǎn)由衰老引起的神經(jīng)發(fā)生能力的減退(很大原因是NPC數(shù)量的減少)[43]?？梢?，sAPPα對成體神經(jīng)發(fā)生是有利的，其正向調(diào)控神經(jīng)發(fā)生。

4.2 AICD負向調(diào)控神經(jīng)發(fā)生 2008年Ma Q H等[44]首次報道了AICD在神經(jīng)發(fā)生方面的作用，并發(fā)現(xiàn)TAG1是APP的功能性配體，TAG1和APP相互作用導(dǎo)致了APP胞內(nèi)結(jié)構(gòu)域AICD的釋放，再在胞內(nèi)支架蛋白Fe65的作用下轉(zhuǎn)運至細胞核，負性調(diào)控胚胎SVZ源性的神經(jīng)發(fā)生。次年，有文獻報道，在人類AD患者腦內(nèi)發(fā)現(xiàn)AICD高水平表達[45]。這進一步說明AICD與AD的發(fā)病機制密切相關(guān)。到2010年，Ghosal k等[46]在內(nèi)源性APP不存在的情況下，排除Aβ及其他APP裂解產(chǎn)物的作用，單看AICD的作用，發(fā)現(xiàn)：AICD損害成體海馬神經(jīng)發(fā)生，且這種破壞作用表現(xiàn)為年齡依賴的方式。在AICD轉(zhuǎn)基因小鼠上，6周時海馬區(qū)成體神經(jīng)發(fā)生未見異常，但從3個月持續(xù)到12個月時，均表現(xiàn)出成體神經(jīng)發(fā)生受損，且這種受損是由于炎癥反應(yīng)導(dǎo)致細胞的增殖和存活能力下降引起的。肖志成研究團隊探討了AICD抑制神經(jīng)發(fā)生的可能機制。其研究結(jié)果表明，AICD作為miR-663的轉(zhuǎn)錄因子，通過miR-663抑制FBXL18和CDK6基因的表達，從而抑制人源的NSCs向神經(jīng)元分化，最終負性調(diào)控神經(jīng)發(fā)生[47]?？梢姡珹ICD無論對胚胎還是成體神經(jīng)發(fā)生都是不利的，其通過不同的機制負向調(diào)控神經(jīng)發(fā)生。

4.3 Aβ雙向調(diào)控神經(jīng)發(fā)生 Haughey等的體外實驗較早的報道了Aβ的大量沉積影響了人大腦皮層的神經(jīng)前體細胞的功能，抑制其增殖和向神經(jīng)元分化，并最終導(dǎo)致細胞凋亡[48]。隨后已經(jīng)有大量的研究用AD模型鼠的體內(nèi)實驗證實Aβ對神經(jīng)發(fā)生的的作用，研究結(jié)果表明SGZ源性的神經(jīng)前體細胞向神經(jīng)元分化的能力及新生神經(jīng)元的存活能力均減退，近而導(dǎo)致神經(jīng)發(fā)生能力受損[49-50]。高濃度Aβ42注射入小鼠側(cè)腦室，可抑制SVZ區(qū)及SGZ區(qū)源性的NSCs的增殖及向神經(jīng)元分化[51-52]。然而，也有文獻報道，在體外實驗中，低濃度寡聚肽的Aβ42能促進胚胎及成體的NSCs向神經(jīng)元分化[53-54]。纖維態(tài)的Aβ(即不溶性Aβ)可減少人胚胎干細胞向神經(jīng)元分化，但增加GFAP+神經(jīng)前體細胞的數(shù)量[55]?？梢?，Aβ對神經(jīng)發(fā)生的影響是比較復(fù)雜的，受其濃度和形態(tài)結(jié)構(gòu)的影響。低濃度寡聚肽的Aβ對神經(jīng)發(fā)生起正向調(diào)節(jié)的作用，高濃度及不溶性Aβ對神經(jīng)發(fā)生起負向調(diào)節(jié)的作用。

因此，這些研究結(jié)果顯示，APP在神經(jīng)發(fā)生過程中具有重要作用，其主要通過影響NSCs的增殖、NSCs/NPCs向神經(jīng)元的分化和新生細胞的存活調(diào)控成體神經(jīng)發(fā)生。sAPPα已顯示出對AD治療的潛在價值。在最近的已修訂的阿爾茲海默病的診斷指南中，已明確將sAPPα及相應(yīng)的分泌酶作為AD早期診斷的生物標(biāo)記物[56],修復(fù)sAPPα有望為AD的治療帶來可能[57]。

5 神經(jīng)發(fā)生的改變與AD的關(guān)系

目前越來越多的研究認為，成體神經(jīng)發(fā)生在正常的記憶功能維持中扮演著重要的作用[58-59]。當(dāng)成體神經(jīng)發(fā)生受損時，則會使某些特定類型的記憶受損，如空間學(xué)習(xí)記憶能力[60-62]，導(dǎo)致空間辨別和記憶能力出現(xiàn)障礙，這恰恰是AD典型的臨床表現(xiàn)之一，提示成體神經(jīng)發(fā)生受損對AD是及其不利的一個因素。與此同時，大量的研究報道了在AD患者和AD模型鼠上發(fā)現(xiàn)成體神經(jīng)發(fā)生受損[63-69]。在衰老和AD患者腦內(nèi)觀察到神經(jīng)前體細胞減少最為明顯[70]；在早發(fā)性AD患者的血漿及腦脊液中檢測到干細胞因子(stem cell factor, SCF,是一種造血生長因子，在腦內(nèi)有支持神經(jīng)發(fā)生的作用)的水平降低[71]；在早發(fā)性AD模型鼠(APPswe/PS1dE9)的SVZ區(qū)及SGZ區(qū)NPC的增殖以及向神經(jīng)元分化的能力減退[65，72]，并在9個月時，這種神經(jīng)發(fā)生的能力減退最為明顯[73]。然而，Demars等[74]研究發(fā)現(xiàn)，在早發(fā)性AD模型鼠的早期，2個月時就發(fā)現(xiàn)SVZ區(qū)及SGZ區(qū)NPC的增殖以及分化能力嚴重受損。此外，在AICD轉(zhuǎn)基因小鼠上發(fā)現(xiàn)，神經(jīng)發(fā)生受損第一次被檢測到是在3個月時，比記憶受損(4～5個月時才出現(xiàn))出現(xiàn)早[75]。在3xTg AD模型鼠上也發(fā)現(xiàn)相似的現(xiàn)象：成體神經(jīng)發(fā)生受損較AD的其他病理特征先檢測出來[76]。因此，這些研究結(jié)果表明，成體神經(jīng)發(fā)生能力受損可能導(dǎo)致了AD患者出現(xiàn)海馬依賴的及嗅球依賴的記憶缺失及認知功能受損。

6 小結(jié)

綜上所述，AD是一種多病因參與的復(fù)雜疾病，神經(jīng)發(fā)生是其中的一個重要因素和關(guān)鍵環(huán)節(jié)。在AD病理進程中起關(guān)鍵作用的分子APP參與了這一重要事件。但由于APP類型的多樣性，以及其水解產(chǎn)物在神經(jīng)發(fā)生方面表現(xiàn)的多樣性，使得將其作為診斷標(biāo)記物及靶向治療的可行性和有效性變得復(fù)雜和困難。盡管目前已將sAPPα作為AD 早期診斷的指標(biāo)及治療方向，但其影響神經(jīng)發(fā)生的作用機制仍未明確。因此，仍需大量的研究來探討APP及其水解產(chǎn)物對神經(jīng)發(fā)生影響的作用機制。后續(xù)研究仍任重道遠。

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The Application and Research Progress of the Role of APP in Neurogenesis and Alzheimer’s Disease

ZHU Hongmei1ZHANG Fenglan1CHEN Fang3*XIAO Zhicheng1,2*
1.Key Laboratory of Stem Cell and Regenerative Medicine of Yunnan Province, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, China; 2. Immunology and Stem Cell Laboratory, Monash University, Melbourne 3800, Australia;3.School of Basic Medicine, Kunming Medical University, Kunming 650500, China

Alzheimer disease, commonly known as Dementia, was first discovered by German surgon Alzheimer. But this Dementia is different from normal aging. It’s a progressive and fatal neurodegenerative disease. Since the discovery of the disease in 1906, its precise pathogenesis has not been completely defined, there is also no an accurate method for early diagnosis and effective treatment.In recent years, a number of studies have confirmed that neurogenesis occurs throughout the central nervous system of adult mammals, which provides hope for the treatment of brain injuries and neurodegenerative diseases such as AD.The study of adult neurogenesis will be great significance for the repair of clinical brain injury and the treatment of AD and other diseases.The article reviewed the process of the central nervous system of adult neurogenesis and the role of APP which is a key molecule involved in pathological process of AD,and summarize its current progress as reference for research.

Amyloid Precursor Protein; Neurogenesis; Alzheimer Disease

朱紅梅(1990-)，女，漢族，碩士研究生在讀，研究方向為神經(jīng)退行性疾病。E-mail：15288180973@163.com

肖志成(1957-)，男，漢族，博士后，教授，研究方向為神經(jīng)分子生物學(xué)。E-mail：zhicheng.xiao@monash.edu

陳 芳(1982-)，女，漢族，雙學(xué)位，講師，研究方向為基礎(chǔ)醫(yī)學(xué)、分子生物學(xué)。E-mail：45972141@qq.com

R747.8

A

1007-8517(2017)12-0074-07

2017-05-25 編輯：陶希睿)