運(yùn)動(dòng)、阿爾茨海默病與突觸可塑性①

劉慧莉，趙剛

阿爾茨海默病(Alzheimer's disease,AD)是一種原發(fā)性神經(jīng)退行性疾病。早期主要的臨床表現(xiàn)為漸進(jìn)性學(xué)習(xí)和記憶能力減退。全球65歲以上人群中約有6%的人罹患此病[1]。由于AD起病隱匿、病因復(fù)雜，目前尚無(wú)特效的治療藥物和手段，因此尋找經(jīng)濟(jì)有效的防治方法日益成為人們關(guān)注的焦點(diǎn)。

運(yùn)動(dòng)是中樞神經(jīng)系統(tǒng)有效的刺激形式。所有運(yùn)動(dòng)都可向中樞神經(jīng)系統(tǒng)提供感覺(jué)、運(yùn)動(dòng)和反射性傳入，運(yùn)動(dòng)對(duì)大腦的功能重組和代償起著重要作用。研究表明，運(yùn)動(dòng)不僅能提高普通人群的認(rèn)知能力，還能減緩AD的發(fā)病和進(jìn)展[2]。

突觸(synapse)是神經(jīng)元間相互接觸部分的功能特化區(qū)，是神經(jīng)元實(shí)現(xiàn)生理功能的關(guān)鍵部位。近年來(lái)，突觸可塑性(synaptic plasticity)的研究引起人們關(guān)注。中樞神經(jīng)系統(tǒng)的突觸可塑性是研究學(xué)習(xí)和記憶神經(jīng)機(jī)制的核心問(wèn)題，突觸可塑性改變可能是運(yùn)動(dòng)防治AD的細(xì)胞機(jī)制。本文綜述運(yùn)動(dòng)對(duì)AD的防治作用、AD突觸可塑性的改變及運(yùn)動(dòng)對(duì)突觸可塑性的影響。

1 運(yùn)動(dòng)對(duì)AD的防治作用

1.1 流行病學(xué)調(diào)查 盡管在一項(xiàng)小樣本調(diào)查中發(fā)現(xiàn)每周體力活動(dòng)時(shí)間與AD發(fā)生的風(fēng)險(xiǎn)無(wú)關(guān)[3]，但是，眾多的研究證明，運(yùn)動(dòng)對(duì)AD有預(yù)防或改善的作用[4-6]。一項(xiàng)追蹤調(diào)查表明，AD患者中年期很少活動(dòng)，缺乏體力活動(dòng)可使AD發(fā)病風(fēng)險(xiǎn)增加250%[5]。前瞻性研究也顯示，體力活動(dòng)能夠?qū)拐J(rèn)知能力損害、AD和任何類型癡呆的進(jìn)展，其中體力活動(dòng)較多的人群，AD發(fā)生率下降60%[6]。

1.2 動(dòng)物實(shí)驗(yàn)研究 在動(dòng)物實(shí)驗(yàn)研究中，運(yùn)動(dòng)的防治效果與運(yùn)動(dòng)類型、運(yùn)動(dòng)強(qiáng)度、運(yùn)動(dòng)開(kāi)始時(shí)間節(jié)點(diǎn)和運(yùn)動(dòng)持續(xù)時(shí)間有關(guān)。跑輪運(yùn)動(dòng)和跑臺(tái)運(yùn)動(dòng)是干預(yù)嚙齒類動(dòng)物的兩種最好的運(yùn)動(dòng)類型。

跑輪運(yùn)動(dòng)被認(rèn)為是一種自愿運(yùn)動(dòng)方式，研究表明，與跑臺(tái)運(yùn)動(dòng)相比，跑輪運(yùn)動(dòng)改善AD行為學(xué)和神經(jīng)病理學(xué)損害更為有效[7]。跑輪運(yùn)動(dòng)對(duì)AD轉(zhuǎn)基因小鼠的認(rèn)知功能和病理過(guò)程的作用仍存在爭(zhēng)議。跑輪運(yùn)動(dòng)減輕TgCRND8轉(zhuǎn)基因小鼠β淀粉樣蛋白(β-amyloid protein,Aβ)斑塊沉積并且改善水迷宮學(xué)習(xí)能力[8]；卻沒(méi)能改善APP23轉(zhuǎn)基因小鼠空間學(xué)習(xí)能力、減少Aβ斑塊沉積和增加海馬神經(jīng)再生[9]。這些矛盾的研究結(jié)果可能與轉(zhuǎn)基因小鼠種類、跑輪運(yùn)動(dòng)開(kāi)始的時(shí)間和運(yùn)動(dòng)持續(xù)時(shí)間有關(guān)。Richter等的研究表明，跑輪運(yùn)動(dòng)可能是轉(zhuǎn)基因小鼠的一種固定行為[10]。

具有電刺激的跑臺(tái)運(yùn)動(dòng)因?yàn)樵黾泳駢毫?，?duì)健康造成負(fù)面影響，被認(rèn)為是一種強(qiáng)制運(yùn)動(dòng)。但也有研究發(fā)現(xiàn)，強(qiáng)制運(yùn)動(dòng)同樣改善神經(jīng)退行性疾病動(dòng)物模型的認(rèn)知功能[11-12]；長(zhǎng)期規(guī)律的跑臺(tái)運(yùn)動(dòng)提高野生型小鼠和轉(zhuǎn)基因小鼠水迷宮任務(wù)的學(xué)習(xí)和記憶能力[13-14]。此外，與單純跑輪運(yùn)動(dòng)相比，豐富環(huán)境訓(xùn)練能更有效地改善AD轉(zhuǎn)基因小鼠的認(rèn)知功能損害，提示多種方式相結(jié)合的運(yùn)動(dòng)訓(xùn)練對(duì)AD的防治更有效[15]。

2 AD的突觸可塑性改變

所謂突觸可塑性是指突觸在一定條件下，調(diào)整功能、改變形態(tài)及增減數(shù)目的能力；它既包括傳遞效能的變化，也包括形態(tài)結(jié)構(gòu)的變化。中樞神經(jīng)系統(tǒng)的突觸可塑性是研究中樞神經(jīng)系統(tǒng)生長(zhǎng)、發(fā)育、蛻變、損傷修復(fù)以及在學(xué)習(xí)和記憶過(guò)程中神經(jīng)機(jī)制的核心問(wèn)題。研究表明，海馬神經(jīng)元的突觸缺失和突觸可塑性變化在老年性癡呆的病理過(guò)程中占據(jù)重要地位，可能是老年性癡呆學(xué)習(xí)和記憶功能障礙的神經(jīng)生物學(xué)基礎(chǔ)[16]。

長(zhǎng)時(shí)程增強(qiáng)(long-term potentiation,LTP)是表現(xiàn)突觸可塑性的重要電生理指標(biāo)。已經(jīng)證實(shí)，不同類型的AD轉(zhuǎn)基因模型出現(xiàn)海馬LTP減弱[17-18]；AD轉(zhuǎn)基因小鼠海馬環(huán)路的突觸傳遞異常早于Aβ沉積和神經(jīng)細(xì)胞變性[19]。攜帶有突變APP695 SWE和PS1ΔE9基因的轉(zhuǎn)基因小鼠，盡管空間學(xué)習(xí)能力下降，但離體海馬腦片誘導(dǎo)的LTP卻未發(fā)生變化[20]。先前的研究發(fā)現(xiàn)，突變基因APP695 SWE和PS1A246E過(guò)表達(dá)的17~18月齡的老年轉(zhuǎn)基因小鼠，在體海馬DG區(qū)LTP減弱，但離體海馬腦片CA1區(qū)LTP不變[21]。此外，不同月齡(2、6、9和14月齡)的野生型小鼠和轉(zhuǎn)基因小鼠離體腦片誘導(dǎo)的LTP未見(jiàn)不同[22]。這些研究的不同結(jié)論可能與實(shí)驗(yàn)方法(在體或離體)和研究通路不同有關(guān)。

突觸蛋白(synapsin)可作為突觸前終末的特異性標(biāo)記物，用來(lái)檢測(cè)突觸的密度和分布。已發(fā)現(xiàn)AD患者腦海馬結(jié)構(gòu)內(nèi)突觸蛋白含量比正常人明顯減少，提示AD患者的海馬神經(jīng)元突觸密度下降[23-24]。Bertoni-Freddari早期研究發(fā)現(xiàn)，皮質(zhì)和海馬突觸聯(lián)系缺失的嚴(yán)重程度與AD的癡呆程度呈正相關(guān)[25]。Masliah等也發(fā)現(xiàn)，與AD臨床癥狀的嚴(yán)重性關(guān)系最密切的是新皮質(zhì)和海馬中突觸的缺失，而不是斑塊負(fù)荷[26]。突觸聯(lián)系缺失在AD早期即可出現(xiàn)，以海馬的齒狀回分子層最嚴(yán)重[27]，而在海馬的其他區(qū)域和新皮質(zhì)區(qū)程度較輕[28]。

3 運(yùn)動(dòng)對(duì)突觸可塑性的作用

神經(jīng)可塑性改變是神經(jīng)損傷后恢復(fù)的基礎(chǔ)。突觸是神經(jīng)可塑性變化的敏感部位，運(yùn)動(dòng)作為一種條件刺激，可引起突觸形態(tài)結(jié)構(gòu)和功能的重塑。

3.1 功能可塑性 電生理學(xué)研究發(fā)現(xiàn)，跑輪運(yùn)動(dòng)和跑臺(tái)運(yùn)動(dòng)都能增強(qiáng)海馬DG區(qū)的LTP[29-30]。4月齡Wistar大鼠連續(xù)跑臺(tái)運(yùn)動(dòng)7 d后，在體記錄海馬DG區(qū)的LTP顯著增強(qiáng)[31]。

運(yùn)動(dòng)對(duì)神經(jīng)系統(tǒng)疾病的有益作用可能與突觸傳遞效能的增強(qiáng)有關(guān)。運(yùn)動(dòng)訓(xùn)練使大腦中動(dòng)脈缺血大鼠海馬CA3區(qū)突觸效應(yīng)的習(xí)得性LTP形成速度明顯快于安靜對(duì)照組[32]。離體腦片電生理記錄發(fā)現(xiàn)，匹魯卡品所致的癲癇大鼠出現(xiàn)海馬CA1區(qū)遲發(fā)型LTP減弱，運(yùn)動(dòng)訓(xùn)練可增強(qiáng)LTP[33]。馬強(qiáng)等發(fā)現(xiàn)，8周跑輪運(yùn)動(dòng)明顯減緩隨后21 d慢性束縛應(yīng)激對(duì)大鼠海馬齒狀回LTP的抑制，認(rèn)為長(zhǎng)期體力運(yùn)動(dòng)對(duì)海馬有神經(jīng)保護(hù)作用，可減緩慢性應(yīng)激引起的損傷[34]。我們?cè)谙惹暗难芯恐幸舶l(fā)現(xiàn)，長(zhǎng)期規(guī)律的跑臺(tái)運(yùn)動(dòng)改善8月齡AD轉(zhuǎn)基因模型小鼠學(xué)習(xí)和記憶功能，同時(shí)伴有LTP增強(qiáng)[14]。

3.2 形態(tài)可塑性 突觸的形態(tài)結(jié)構(gòu)對(duì)突觸功能狀態(tài)和神經(jīng)信息傳遞有重要影響，是學(xué)習(xí)和記憶能力的結(jié)構(gòu)基礎(chǔ)；促進(jìn)突觸形態(tài)可塑性的發(fā)揮，對(duì)AD的學(xué)習(xí)和記憶能力的改善具有重要意義。關(guān)于運(yùn)動(dòng)對(duì)突觸形態(tài)可塑性影響的研究較少。大鼠進(jìn)行8周游泳訓(xùn)練后，其大腦皮質(zhì)運(yùn)動(dòng)區(qū)V層的大椎體細(xì)胞的胞體、核仁、樹(shù)突棘密度均顯著高于安靜對(duì)照組，說(shuō)明適宜運(yùn)動(dòng)對(duì)大腦皮質(zhì)神經(jīng)元的形態(tài)結(jié)構(gòu)可能產(chǎn)生良好的影響，提高大腦對(duì)信息的處理能力[35]。關(guān)于運(yùn)動(dòng)影響突觸形態(tài)可塑性的研究多集中于腦缺血康復(fù)治療的實(shí)驗(yàn)研究中。Briones等發(fā)現(xiàn)，腦缺血損傷大鼠經(jīng)過(guò)運(yùn)動(dòng)訓(xùn)練后，不僅增加海馬齒狀回的神經(jīng)發(fā)生[36]，同時(shí)促進(jìn)齒狀回突觸形態(tài)可塑性的改變，表現(xiàn)為突觸密度增加、多樣性突觸出現(xiàn)以及穿孔突觸數(shù)量增加等[37-38]。右側(cè)大腦中動(dòng)脈缺血梗死模型大鼠進(jìn)行多種方式運(yùn)動(dòng)訓(xùn)練，5周后透射電鏡觀察健側(cè)大腦感覺(jué)運(yùn)動(dòng)皮質(zhì)和海馬CA3區(qū)突觸結(jié)構(gòu)發(fā)生可塑性變化，突觸界面曲率、突觸后致密物厚度和穿孔突觸數(shù)量明顯增加，改善了腦缺血大鼠學(xué)習(xí)和記憶功能[39]。

4 小結(jié)

突觸的病理性重構(gòu)是AD學(xué)習(xí)和記憶能力下降的病理基礎(chǔ)之一；運(yùn)動(dòng)作為中樞神經(jīng)系統(tǒng)最有效的刺激形式，對(duì)突觸結(jié)構(gòu)和功能的重組具有重要作用。采用不同運(yùn)動(dòng)方式、運(yùn)動(dòng)強(qiáng)度及運(yùn)動(dòng)開(kāi)始干預(yù)的時(shí)間節(jié)點(diǎn)，研究運(yùn)動(dòng)對(duì)AD的防治效果以及運(yùn)動(dòng)防治AD的細(xì)胞機(jī)制具有重要意義。

運(yùn)動(dòng)對(duì)AD的干預(yù)是一個(gè)多機(jī)制的復(fù)雜過(guò)程，需要從行為學(xué)、電生理學(xué)、神經(jīng)病理學(xué)、分子生物學(xué)等多個(gè)角度全面、深入地闡釋運(yùn)動(dòng)防治AD的細(xì)胞和分子機(jī)制，為AD治療的臨床實(shí)踐提供理論基礎(chǔ)。

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