腦衰老相關(guān)認(rèn)知損傷研究進(jìn)展

陳琛李素霞孟適秋1閆薇1孫洪強(qiáng)1陸林1

(北京大學(xué)中國(guó)藥物依賴性研究所，北京100191)

關(guān)鍵詞〔〕腦衰老；認(rèn)知功能；突觸可塑性；蛋白質(zhì)合成；表觀遺傳

中圖分類號(hào)〔〕R74〔

基金項(xiàng)目：國(guó)家自然科學(xué)基金面上項(xiàng)目(81171251)

通訊作者：李素霞(1970-)，女，副研究員，博士，主要從事生物精神病學(xué)研究。

1北京大學(xué)第六醫(yī)院

第一作者：陳琛(1987-)，男，博士在讀，主要從事衰老相關(guān)認(rèn)知損傷研究。

生物醫(yī)藥科技的發(fā)展，有效治療了青年和中年群體的疾病，使得他們的期望壽命明顯延長(zhǎng)，也增加了老年人口數(shù)量的比例〔1〕。與此同時(shí)增加了認(rèn)知功能受損和老年癡呆的潛在受累人數(shù)，這一人數(shù)將隨著人口平均年齡的增加而持續(xù)增長(zhǎng)。然而，目前對(duì)于衰老相關(guān)認(rèn)知功能損傷的原因及調(diào)控機(jī)制的認(rèn)識(shí)并不透徹，導(dǎo)致缺乏有效的改善方法和預(yù)防措施。因此，了解衰老相關(guān)認(rèn)知損傷的神經(jīng)生物學(xué)機(jī)制就十分重要。

1衰老相關(guān)的認(rèn)知功能損傷

人類生長(zhǎng)發(fā)育到成熟期以后，隨著年齡的增長(zhǎng)，腦內(nèi)髓鞘發(fā)育生成受損，神經(jīng)細(xì)胞萎縮，細(xì)胞內(nèi)脂褐素蓄積，突觸聯(lián)系和神經(jīng)遞質(zhì)減少，接受和傳遞信息的能力降低，導(dǎo)致老年人感覺(jué)遲鈍、反應(yīng)緩慢、記憶力下降、腦功能降低，這一現(xiàn)象就是腦衰老。認(rèn)知功能受腦衰老影響尤為嚴(yán)重。早先的橫斷面研究提示，語(yǔ)音信息延遲和喚起能力降低廣泛存在于老年人群〔2〕；同樣，工作記憶和短時(shí)程喚起能力也會(huì)隨衰老而降低〔3〕。衰老相關(guān)記憶損傷的另一表現(xiàn)，是空間記憶能力的降低，這一現(xiàn)象普遍存在于包括人類、靈長(zhǎng)類、犬科動(dòng)物和嚙齒類動(dòng)物在內(nèi)的多個(gè)物種〔4～7〕。功能性磁共振成像和正電子斷層掃描研究發(fā)現(xiàn)，衰老相關(guān)記憶改變與前額葉皮層和海馬兩個(gè)腦區(qū)的活性改變呈相關(guān)性。執(zhí)行功能相關(guān)任務(wù)測(cè)試時(shí)，老年組前額葉皮層活性低于青年組〔8〕。通常老年人在認(rèn)知損傷時(shí)，會(huì)通過(guò)激活更大面積的前額葉皮層充當(dāng)補(bǔ)償機(jī)制〔9〕。在海馬腦區(qū)中，齒狀回是受衰老影響最嚴(yán)重的亞區(qū)〔10〕。正常狀態(tài)下與病理狀態(tài)下，衰老所致的記憶損傷同樣存在差異。腦結(jié)構(gòu)研究發(fā)現(xiàn)，中顳葉體積縮小與阿爾茨海默病患者記憶受損有關(guān)，該腦區(qū)體積縮小最早可于記憶損傷的最初期出現(xiàn)；而前額葉皮層體積縮小與正常衰老所致的認(rèn)知損傷相關(guān)〔11〕。

1.1海馬腦區(qū)調(diào)控的記憶范式海馬和前額葉皮層對(duì)衰老存在較高易感性。所以，經(jīng)此腦區(qū)調(diào)控的任務(wù)處理能力會(huì)隨著年齡的增加出現(xiàn)相應(yīng)降低。海馬是調(diào)控情景記憶和空間記憶的主要腦區(qū)〔12〕。在人群研究中發(fā)現(xiàn)，老年人的情景記憶受損，表現(xiàn)為記憶相關(guān)的環(huán)境細(xì)節(jié)喚起障礙〔13,14〕。老年人在使用幻燈片模擬空間穿越學(xué)習(xí)時(shí)，會(huì)出現(xiàn)明顯的空間記憶受損。研究發(fā)現(xiàn)，損傷海馬腦區(qū)會(huì)導(dǎo)致包括嚙齒動(dòng)物、靈長(zhǎng)類動(dòng)物和人類〔15〕在內(nèi)多個(gè)物種的空間記憶損傷。Morris水迷宮是檢測(cè)空間記憶的經(jīng)典動(dòng)物模型，嚙齒類動(dòng)物由于逃生動(dòng)機(jī)的驅(qū)使，會(huì)很快記住平臺(tái)的位置并登上平臺(tái)，登上平臺(tái)所需時(shí)間以及游泳的距離被用于評(píng)價(jià)學(xué)習(xí)記憶能力；衰老大鼠經(jīng)過(guò)多天訓(xùn)練后，其搜索平臺(tái)能力會(huì)增強(qiáng)，但測(cè)試結(jié)果明顯低于青年組〔16〕。

海馬腦區(qū)在環(huán)境性恐懼記憶的調(diào)控中，同樣發(fā)揮關(guān)鍵作用，而杏仁核腦區(qū)同時(shí)參與環(huán)境性和線索誘導(dǎo)的恐懼記憶的調(diào)控〔17〕。研究發(fā)現(xiàn)，與衰老組相比，青年組的右側(cè)杏仁核和海馬腦區(qū)激活程度更高;衰老大鼠的記憶獲得能力完整，而長(zhǎng)時(shí)程記憶的鞏固能力受損〔18,19〕。痕跡眨眼條件反射模型屬于海馬腦區(qū)調(diào)控的另一條件反射模型：聲音作為條件性刺激，而對(duì)眼睛吹氣屬于非條件性刺激。習(xí)得眨眼條件反射所需的時(shí)間，以及這種記憶維持的時(shí)間均作為檢測(cè)指標(biāo)。研究發(fā)現(xiàn)，衰老的小鼠、大鼠、兔子和人類在痕跡眨眼條件反射記憶的獲得和維持中均出現(xiàn)損傷〔20～24〕。

1.2前額葉皮層調(diào)控的記憶范式前額葉皮層在調(diào)控執(zhí)行功能中發(fā)揮重要作用，注意力、抑制力、工作記憶、認(rèn)知靈活性和決策力均屬于執(zhí)行功能的范疇〔25～27〕。與嚙齒類動(dòng)物相比，靈長(zhǎng)類動(dòng)物的前額葉皮層結(jié)構(gòu)要明顯復(fù)雜，所以也曾認(rèn)為執(zhí)行功能是靈長(zhǎng)類獨(dú)有的特征。然而，大量研究證明嚙齒類動(dòng)物具有與靈長(zhǎng)類同源的神經(jīng)解剖和功能特性；并且能夠完成一系列復(fù)雜的、目標(biāo)明確的行為〔28～30〕。

工作記憶被視作一種復(fù)雜的認(rèn)知過(guò)程，需要前額葉皮層的參與，并且對(duì)年齡因素易感性強(qiáng)。工作記憶的經(jīng)典范式為空間延遲喚起實(shí)驗(yàn)，毀損人類和靈長(zhǎng)類背外側(cè)前額葉皮層，能夠損傷此類記憶〔31,32〕；當(dāng)延遲時(shí)間逐漸增加，老年組的學(xué)習(xí)能力明顯低于青年組〔27〕。在嚙齒類動(dòng)物中，研究工作記憶常用的行為學(xué)模型包括：Torris迷宮，八臂迷宮等。Torris迷宮時(shí)間延遲依賴的任務(wù)中，老年組在長(zhǎng)時(shí)間延遲中出現(xiàn)的錯(cuò)誤探索次數(shù)明顯高于青年組〔33〕。八臂迷宮測(cè)試也得到相似的結(jié)果，老年組探索已選臂的次數(shù)顯著高于青年組，隨著延遲時(shí)間的增加，錯(cuò)誤臂的探索次數(shù)也隨之增加〔34,35〕。在大鼠延遲喚起的水迷宮任務(wù)中，發(fā)現(xiàn)相似的結(jié)果：延遲為30 min時(shí)，老年組到達(dá)平臺(tái)所需時(shí)間與青年組無(wú)差異；延遲從2 h增加至6 h，老年組到達(dá)平臺(tái)所需時(shí)間逐漸增加，且與青年組有明顯差異〔36〕。

認(rèn)知靈活性是指：當(dāng)先前獲得的信息或者反應(yīng)條件已不適應(yīng)新的狀態(tài)時(shí)，做出的抑制性反應(yīng)。這一能力依賴于前額葉皮層，并且存在年齡易感性〔37〕。人類和靈長(zhǎng)類研究發(fā)現(xiàn)：當(dāng)先前獎(jiǎng)賞相關(guān)的線索已變成無(wú)效線索時(shí)，老年組很難做出適應(yīng)性的調(diào)整〔38〕；用嚙齒動(dòng)物所做研究，也得到相似的結(jié)果〔39〕。

Dias等〔40〕對(duì)威斯康星卡牌分類實(shí)驗(yàn)(WCST)進(jìn)行修改，使其可用于靈長(zhǎng)類動(dòng)物。其中包括兩種行為轉(zhuǎn)換：內(nèi)維度轉(zhuǎn)換(IDS)和外維度轉(zhuǎn)換(EDS)，IDS是指對(duì)于兩個(gè)顏色和形狀均不同的物體，受試者最初選擇用顏色區(qū)分，那么隨后任務(wù)中也要用顏色作區(qū)分；而EDS則是在隨后的任務(wù)中用形狀作區(qū)分。研究發(fā)現(xiàn)：損毀背外側(cè)前額葉皮層能夠損傷EDS任務(wù)。采用擬人類 WCST也可用于檢測(cè)嚙齒類動(dòng)物前額葉認(rèn)知靈活性的注意定勢(shì)轉(zhuǎn)移任務(wù)。研究發(fā)現(xiàn)，衰老組的IDS任務(wù)表現(xiàn)與青年組相比，差異無(wú)統(tǒng)計(jì)學(xué)意義；而青年組EDS任務(wù)表現(xiàn)則明顯優(yōu)于衰老組〔41〕。

2衰老相關(guān)認(rèn)知功能損傷的神經(jīng)生物學(xué)機(jī)制

2.1突觸可塑性缺失與衰老相關(guān)的認(rèn)知損傷突觸可塑性的改變是衰老相關(guān)認(rèn)知功能下降可能的調(diào)控因素之一。皮層和海馬腦區(qū)的樹(shù)突棘與突觸數(shù)量會(huì)因衰老而發(fā)生變化。人類和靈長(zhǎng)類的研究發(fā)現(xiàn)，衰老組額葉皮層的突觸密度降低與任務(wù)測(cè)試時(shí)表現(xiàn)出的活性降低呈正相關(guān)〔42,43〕。衰老同樣能夠?qū)е麓笫蠛ｑR齒狀回區(qū)的突觸數(shù)量減少〔44〕；該腦區(qū)突觸數(shù)量減少是衰老大鼠空間記憶損傷的可能機(jī)制。大鼠海馬腦區(qū)長(zhǎng)時(shí)程增強(qiáng)的誘導(dǎo)和維持會(huì)因衰老而減弱，相反長(zhǎng)時(shí)程抑制的誘導(dǎo)會(huì)因衰老而易化〔45〕。突觸可塑性也受到神經(jīng)元鈣離子濃度的調(diào)控。衰老大鼠神經(jīng)元的鈣離子內(nèi)穩(wěn)態(tài)被破壞會(huì)導(dǎo)致突觸可塑性的改變。衰老大鼠海馬CA1腦區(qū)的電壓門(mén)控鈣離子內(nèi)流增加，這一變化會(huì)損傷神經(jīng)元細(xì)胞內(nèi)的離子緩沖能力〔46〕。在人類和靈長(zhǎng)類研究發(fā)現(xiàn)，衰老組皮層神經(jīng)元對(duì)鈣結(jié)合蛋白1的免疫反應(yīng)性降低〔47〕。衰老個(gè)體前額葉皮層的鈣結(jié)合蛋白1的mRNA表達(dá)水平降低，這一變化會(huì)影響鈣離子的內(nèi)穩(wěn)態(tài)以及突觸可塑性〔48〕。

2.2蛋白質(zhì)合成能力下降與衰老相關(guān)的認(rèn)知損傷早在60年代，F(xiàn)lexner等〔49～51〕發(fā)現(xiàn)，顳葉腦區(qū)新的蛋白質(zhì)合成是長(zhǎng)時(shí)程記憶表達(dá)所必需，并提示新皮層腦區(qū)的蛋白合成為記憶鞏固階段所必需。隨著研究的逐步深入，研究者發(fā)現(xiàn)：在環(huán)境性恐懼記憶和抑制回避模型訓(xùn)練后，立即給予大鼠或小鼠腦區(qū)注射蛋白酶合成抑制劑茴香霉素，能夠損傷長(zhǎng)時(shí)程記憶(訓(xùn)練后24 h測(cè)試)〔52,53〕。小鼠的社會(huì)認(rèn)知模型也得到了相似的結(jié)果〔54〕。編碼長(zhǎng)時(shí)程記憶需要新的蛋白質(zhì)合成，然而，這一合成能力同樣會(huì)隨著衰老而逐漸降低。為此，F(xiàn)lexner等〔49〕提出：隨年齡增加導(dǎo)致蛋白質(zhì)合成減少，可能是衰老所致認(rèn)知功能降低的原因。隨著實(shí)驗(yàn)方法的逐步改進(jìn)，研究者們發(fā)現(xiàn)：在嚙齒動(dòng)物腦中，蛋白合成從出生開(kāi)始增加，至6個(gè)月達(dá)到頂峰，之后逐漸降低〔55～57〕，但是，也有研究者對(duì)出現(xiàn)降低的時(shí)間提出異議〔58〕。盡管如此，研究者們?nèi)詫?duì)于衰老導(dǎo)致蛋白翻譯減少這一觀點(diǎn)持肯定態(tài)度。

其他研究者發(fā)現(xiàn)，在衰老動(dòng)物中，記憶鞏固階段蛋白合成的時(shí)間窗出現(xiàn)改變。Davis等〔59〕研究發(fā)現(xiàn)：不同年齡段小鼠(2～3月齡，6～7月齡，14～15月齡)訓(xùn)練抑制性回避任務(wù)后，即刻注射蛋白酶合成抑制劑茴香霉素，能夠損傷3個(gè)年齡組動(dòng)物7 d后的長(zhǎng)時(shí)程記憶；然而，在訓(xùn)練前10 min注射，僅能損傷14～15月齡組7 d后的長(zhǎng)時(shí)程記憶。隨后，Mizumori等〔60,61〕豐富了Davis等的實(shí)驗(yàn)：增加了17～20月齡組，并且在訓(xùn)練后20和30 min注射，得到相同結(jié)果。上述結(jié)果提示：記憶鞏固過(guò)程在衰老小鼠腦中變得緩慢，這種緩慢的蛋白合成可能損傷記憶鞏固。

后續(xù)研究的重點(diǎn)逐漸轉(zhuǎn)移到轉(zhuǎn)錄調(diào)控水平：即早基因(IEG)具有激活迅速、一過(guò)性調(diào)控突觸活性以及蛋白合成的特點(diǎn)〔62,63〕。IEG可分為兩類：一類為可誘導(dǎo)的轉(zhuǎn)錄因子，另一類為可誘導(dǎo)的效應(yīng)因子。研究發(fā)現(xiàn)，調(diào)控轉(zhuǎn)錄因子zif268可以調(diào)控晚期長(zhǎng)時(shí)程增強(qiáng)和激活基因轉(zhuǎn)錄調(diào)控，在海馬依賴的學(xué)習(xí)記憶中發(fā)揮關(guān)鍵作用〔64,65〕。衰老研究發(fā)現(xiàn)，衰老大鼠海馬CA1腦區(qū)zif268 mRNA水平降低，同時(shí)行為學(xué)測(cè)試顯示空間記憶能力降低〔66,67〕。另一調(diào)控轉(zhuǎn)錄因子c-fos的表達(dá)水平，也會(huì)隨衰老而改變，但是研究結(jié)果并不一致〔68〕?；钚砸蕾嚨募?xì)胞骨架相關(guān)蛋白為效應(yīng)因子蛋白，參與樹(shù)突可塑性，如果抑制Arc活性，能夠選擇性的阻斷長(zhǎng)時(shí)程增強(qiáng)(LTP)的維持及損傷長(zhǎng)時(shí)程記憶〔69〕。同時(shí)，發(fā)現(xiàn)Arc表達(dá)水平隨衰老而降低，與衰老所致的認(rèn)知損傷呈正相關(guān)〔10,70〕。

近期研究發(fā)現(xiàn)，cAMP反應(yīng)原件蛋白(CREB)活性的改變，可能是衰老相關(guān)認(rèn)知損傷的調(diào)控因子之一。CREB能夠參與海馬依賴的記憶鞏固〔71～73〕。學(xué)習(xí)任務(wù)和LTP能夠誘導(dǎo)CREB的活性形式，即磷酸化的CREB(pCREB)〔74,75〕表達(dá)增加。pCREB在衰老的嚙齒動(dòng)物腦中含量降低，Monti等〔76〕發(fā)現(xiàn)：對(duì)5月齡和30月齡的大鼠，進(jìn)行恐懼記憶訓(xùn)練，24 h后檢測(cè)長(zhǎng)時(shí)程記憶，衰老組出現(xiàn)認(rèn)知損傷且pCREB/CREB比值明顯低于5月齡組。CREB共活化因子-CREB結(jié)合蛋白(CBP)在衰老大鼠海馬腦區(qū)含量也出現(xiàn)降低〔77〕。對(duì)3和15月齡大鼠腦區(qū)過(guò)表達(dá)CREB的研究發(fā)現(xiàn)，3月齡動(dòng)物的空間記憶和抑制回避記憶沒(méi)有變化，而15月齡大鼠的任務(wù)相關(guān)記憶有明顯增強(qiáng)〔78〕；過(guò)表達(dá)cAMP抑制因子誘導(dǎo)性CAMP早期抑制劑(ICER)能夠降低1 d和3 d的長(zhǎng)時(shí)程記憶維持，而不影響訓(xùn)練后10 min的短時(shí)程記憶。大量研究結(jié)果提示，衰老動(dòng)物調(diào)控蛋白合成能力的下降，導(dǎo)致了長(zhǎng)時(shí)程記憶能力的受損。

2.3表觀遺傳與衰老相關(guān)的認(rèn)知損傷表觀遺傳學(xué)機(jī)制，對(duì)神經(jīng)系統(tǒng)功能調(diào)控發(fā)揮著重要作用。DNA甲基化和組蛋白乙?；潜碛^遺傳學(xué)中兩種重要的調(diào)控方式，主要通過(guò)動(dòng)態(tài)可逆的調(diào)控核染色質(zhì)重塑過(guò)程調(diào)控基因表達(dá)。直到1983年，發(fā)現(xiàn)異常的DNA甲基化參與腫瘤細(xì)胞生長(zhǎng)〔79〕，這類調(diào)控機(jī)制才逐漸成為研究的焦點(diǎn)。

DNA甲基化是指在DNA甲基轉(zhuǎn)移酶(DNMT)調(diào)控下，胞嘧啶的5'碳端連接上甲基的過(guò)程，該修飾會(huì)沉默DNA轉(zhuǎn)錄和抑制下游蛋白的翻譯〔80〕。研究者們發(fā)現(xiàn)，環(huán)境恐懼訓(xùn)練能夠增加海馬腦區(qū)DNMT的表達(dá)，提高記憶抑制基因PP1甲基化的程度，減少PP1蛋白的翻譯水平；去甲基化和轉(zhuǎn)錄激活突觸可塑性基因reelin及腦源性神經(jīng)營(yíng)養(yǎng)因子(BDNF)的活性，進(jìn)而調(diào)控海馬依賴的長(zhǎng)時(shí)程記憶的表達(dá)和維持〔81,82〕。Miller等〔83〕在前額葉皮層也有相似的發(fā)現(xiàn)：環(huán)境恐懼記憶的訓(xùn)練能夠誘導(dǎo)鈣調(diào)磷酸酶CaN基因高甲基化，降低CaN蛋白的表達(dá)，DNMT抑制劑能夠干擾長(zhǎng)時(shí)程記憶的維持以及調(diào)控CaN甲基化水平。隨后，Oliveira等〔84〕發(fā)現(xiàn)，衰老小鼠的Dnmt3a2含量低于青年小鼠，外源性補(bǔ)充Dnmt3a2，能夠逆轉(zhuǎn)衰老所致海馬依賴性認(rèn)知功能的損傷，這一結(jié)果提示，DNA甲基化從轉(zhuǎn)錄前水平調(diào)控下游功能蛋白的水平，影響了衰老相關(guān)認(rèn)知功能。

3衰老相關(guān)的認(rèn)知功能損傷的預(yù)防

鍛煉身體不僅能夠降低心血管類疾病的發(fā)病率，還能直接促進(jìn)認(rèn)知功能，其調(diào)控機(jī)制包括：增加BDNF和其他神經(jīng)生長(zhǎng)因子的含量〔85,86〕。人群研究發(fā)現(xiàn)，長(zhǎng)時(shí)間的有氧運(yùn)動(dòng)能夠增強(qiáng)70～81歲年齡段女性的認(rèn)知能力〔87〕。動(dòng)物研究發(fā)現(xiàn)，豐富環(huán)境飼養(yǎng)對(duì)小鼠認(rèn)知的改善優(yōu)于單純的有氧運(yùn)動(dòng)〔88〕。

降低氧化應(yīng)激對(duì)DNA和其他大分子的損傷，是減緩衰老的理論治療靶點(diǎn)之一。但實(shí)際操作存在很大的局限性：自由基的清除因子需要在腦內(nèi)維持很高的濃度，才能有效改善氧化應(yīng)激。流行病學(xué)調(diào)查發(fā)現(xiàn)，阿爾茨海默病患者飲食中添加大量維生素E或者選擇性的單胺氧化酶抑制劑，能夠在一定程度上改善認(rèn)知損傷〔89〕。動(dòng)物研究發(fā)現(xiàn)，衰老大鼠飲食中添加線粒體代謝合成產(chǎn)物乙?；笮鯄A和抗氧化劑硫辛酸鹽，能夠促進(jìn)空間記憶，防止線粒體結(jié)構(gòu)退化〔90〕。大鼠注射乙酰輔酶Q10，即線粒體電子傳遞鏈因子，能夠起到神經(jīng)保護(hù)作用〔91〕。

對(duì)蠕蟲(chóng)、果蠅和小鼠的研究發(fā)現(xiàn),限制卡路里攝入能夠明顯延長(zhǎng)壽命，并且促進(jìn)機(jī)體對(duì)抗一系列衰老相關(guān)的病理變化。調(diào)控機(jī)制可能是通過(guò)調(diào)節(jié)去乙?；讣易寤虻谋磉_(dá)而實(shí)現(xiàn)〔92〕。研究證實(shí)：限制卡路里攝入能夠改善嚙齒動(dòng)物和人類衰老所致的學(xué)習(xí)記憶功能損傷〔93,94〕。

4展望

通過(guò)研究發(fā)現(xiàn)，在衰老影響的諸多腦區(qū)中，海馬和前額葉皮層尤為易感。腦區(qū)特異性的突觸可塑性改變，以及調(diào)節(jié)信號(hào)通路中關(guān)鍵因子的轉(zhuǎn)錄和翻譯水平的變化，可能是衰老相關(guān)認(rèn)知功能損傷的主要誘因。全面深入了解衰老大腦信號(hào)傳導(dǎo)、轉(zhuǎn)錄和翻譯的調(diào)控機(jī)制，有助于清晰的認(rèn)識(shí)腦衰老，以及腦衰老相關(guān)的認(rèn)知損傷。如何將分子實(shí)驗(yàn)、動(dòng)物實(shí)驗(yàn)以及臨床實(shí)驗(yàn)多層面研究結(jié)果相結(jié)合，探索出有效的預(yù)防、改善衰老相關(guān)認(rèn)知損傷的方法，是未來(lái)研究的重點(diǎn)。

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〔2014-07-20修回〕

(編輯安冉冉/張慧)