阿爾茨海默病的遺傳學(xué)研究進(jìn)展

高 珊 陳 超 李志鵬 楊 澤

※為通訊作者

阿爾茨海默病的遺傳學(xué)研究進(jìn)展

高 珊1,2陳 超2※李志鵬2楊 澤1※

阿爾茨海默病(Alzheimer’s disease，AD)是一種常見的中樞神經(jīng)性退行性疾病。普遍認(rèn)為AD的發(fā)生是遺傳、環(huán)境、代謝等多種因素共同作用的結(jié)果。自20世紀(jì)末AD的研究進(jìn)入到分子遺傳學(xué)和基因組學(xué)的水平以來，陸續(xù)發(fā)現(xiàn)了一些AD的易感基因。本文將就2016年至今AD易感基因(ABCA7，APOE，CLU，ESR2，CR1，INPP5D，BIN1，CD2AP，PICALM，SLC242A，APP，MTHFR，PSEN1，PSEN2，SORL1，PTK2B，TOMM40，PTGS2，ZCWPW1，F(xiàn)ERMT2)的遺傳學(xué)研究進(jìn)展作一綜述。

阿爾茨海默病 易感基因

阿爾茨海默病(Alzheimer’s disease，AD)是一種常見的中樞神經(jīng)性退行性疾病，包括進(jìn)行性記憶衰退、認(rèn)知功能下降、行為異常和社交功功能障礙。AD大多發(fā)生在65歲以上的患者，且世界范圍內(nèi)的發(fā)生趨勢也成指數(shù)上漲，從60歲中段人群中的2%到80歲人群的30%至35%[1]，嚴(yán)重威脅老年人的健康。AD的發(fā)病原因及機(jī)制尚不明確，普遍認(rèn)為AD的發(fā)生是多種因素共同作用的結(jié)果，包括遺傳、環(huán)境、代謝等多種因素，其中遺傳因素起重要作用。

自20世紀(jì)末，Goate A等人發(fā)現(xiàn)了早發(fā)型阿爾茨海默病患者21號染色體上APP基因發(fā)生突變[2]，這標(biāo)志著AD的研究進(jìn)入到分子遺傳學(xué)和基因組學(xué)的水平。近些年隨著全基因組關(guān)聯(lián)研究(genome-wide association study,GWAS)和第二代基因測序技術(shù)(next generation sequencing,NGS)的蓬勃發(fā)展，又陸續(xù)發(fā)現(xiàn)了一些新的AD易感基因。目前已知與AD相關(guān)聯(lián)的基因至少有50個(gè)[3]，不同基因分別對應(yīng)家族性早發(fā)、家族性晚發(fā)和散發(fā)性晚發(fā)三類AD。本文將就2016年至今AD易感基因的遺傳學(xué)研究進(jìn)展作一綜述。

1.脂代謝相關(guān)基因

1.1 ABCA7基因 ABCA7基因編碼ATP結(jié)合盒(ABC)轉(zhuǎn)運(yùn)蛋白的超家族成員，在單核細(xì)胞和巨噬細(xì)胞中高度表達(dá)，參與分子的跨膜轉(zhuǎn)運(yùn)，并受膽固醇的調(diào)節(jié)，這表明其在慢性炎癥性疾病的作用。通過對人腦組織的研究[4,5]，AD患者的ABCA7基因存在功能的潛在損失[6]。最近GWAS研究發(fā)現(xiàn)，ABCA7基因上的多肽位點(diǎn)rs4147929，rs200538373，rs142076058，rs376824416，rs78117248，rs3764650，rs3764605，rs7408475，rs3752246會增加AD的患病風(fēng)險(xiǎn)。

1.2 APOE基因 APOE基因是目前已被證實(shí)的散發(fā)性、遲發(fā)性(年齡>60)以及常染色體顯性家族性AD的易感基因[7,8]。APOE基因的三個(gè)常見多態(tài)性，ε2，ε3和ε4導(dǎo)致了ApoE蛋白中的單個(gè)氨基酸變化且有強(qiáng)相關(guān)性改變發(fā)生阿爾茨海默病(AD)的可能性。AD的風(fēng)險(xiǎn)與APOE的等位基因相關(guān)(ε4>ε3>ε2)，特別地，APOEε4與遲發(fā)性AD的風(fēng)險(xiǎn)增加相關(guān)約占患者的50%，APOEε2與遲發(fā)性AD的風(fēng)險(xiǎn)降低相關(guān)[7,9,10]。APOE不同的基因型對AD風(fēng)險(xiǎn)的影響很大程度上是ApoE蛋白對腦和腦血管中淀粉樣蛋白β(Aβ)的積累產(chǎn)生的不同影響。但需要注意的是APOEε4對AD病程的發(fā)展不是充要條件，因此apoE的多態(tài)性不能單獨(dú)用來診斷AD[11,12]。

1.3 CLU基因 CLU基因也為ApoJ基因，是晚發(fā)性AD易感基因之一[13]。CLU基因高度保守，并且廣泛表達(dá)，其參與細(xì)胞周期、炎癥反應(yīng)、脂質(zhì)運(yùn)輸、膜循環(huán)和細(xì)胞凋亡、激活神經(jīng)元營養(yǎng)因子并促進(jìn)神經(jīng)元存貨[14]。CLU表達(dá)的叢集素與Aβ結(jié)合并阻止Aβ聚集[15,16]，并且叢集素能增強(qiáng)溶酶體對Aβ的降解[17，18]，并通過血腦屏障清除Aβ[17]。通過GWAS分析研究，CLU基因上的多肽位點(diǎn)rs9331896，rs2279590，rs9331888，rs11136000，rs9331942，rs7831810，rs1532277與AD相關(guān)，而對CLU及其相關(guān)基因的研究對AD進(jìn)程的研究有重要意義。

1.4 ESR2基因 雌激素是不僅對生殖系統(tǒng)，而且對中樞神經(jīng)系統(tǒng)有影響的多效激素。目前，有人認(rèn)為星形膠質(zhì)細(xì)胞合成和分泌的雌激素可以調(diào)節(jié)突觸形成和突觸傳遞[19]。在過去幾十年中，已經(jīng)發(fā)表了關(guān)于雌激素在中樞神經(jīng)系統(tǒng)中的有益作用的一些研究[20,21]。此外，雌激素與氧化應(yīng)激保護(hù)、神經(jīng)遞質(zhì)調(diào)節(jié)、情緒障礙和基因表達(dá)有關(guān)[22～24]。另一方面，女性絕經(jīng)后雌激素水平降低是AD的重要危險(xiǎn)因素[25,26]。然而，雌激素與AD相關(guān)的主要機(jī)制仍然未知。雌激素代謝物結(jié)合雌激素受體(ERs)，其屬于作為配體激活轉(zhuǎn)錄因子的核激素受體的超家族[27,28]。ESR2基因編碼ERs的亞型ERβ。ERβ參與情感、情緒、行為和認(rèn)知的調(diào)節(jié)，這都對AD產(chǎn)生影響[29,30]。此外，現(xiàn)在已經(jīng)認(rèn)識到雌激素通過ER亞型的不同激活影響ApoE水平[31,32]。ESR2基因中的一些在以前的研究中已經(jīng)與AD相關(guān)，并且它們似乎參與基因增強(qiáng)子活性或基因調(diào)控[33,34]。研究表明，ESR2基因多態(tài)性與AD發(fā)病晚期有關(guān)[35]，該基因的變異可能改變疾病易感性。

1.5 PTGS2基因 編碼PTGS2的基因位于1q31.1在兩個(gè)與阿爾茨海默病相關(guān)的區(qū)域之間[69]。PTGS2基因也稱為環(huán)加氧酶2基因(COX2),已被證明在中樞神經(jīng)系統(tǒng)的炎性細(xì)胞中被普遍表達(dá)[70]。

表1 AD脂代謝相關(guān)易感基因

續(xù)表1

2.免疫調(diào)節(jié)相關(guān)基因——CR1基因

CR1基因是補(bǔ)體激活(RCA)家族的受體成員，位于1號染色體的“簇RCA”區(qū)域。在GWAS研究中，CR1基因被認(rèn)為是AD的風(fēng)險(xiǎn)基因[36]。CR1表達(dá)的凝集素蛋白在聚集和沉積中，直接影響Aβ。凝集素的存在會影響Aβ的形態(tài)和毒性[37,38]。凝集素可調(diào)節(jié)可溶性Aβ向不溶性的形式轉(zhuǎn)化，如低聚物的轉(zhuǎn)化，從而抑制Aβ的毒性和沉積。凝集素參與Aβ交叉形成復(fù)雜的血腦屏障，其可調(diào)節(jié)Aβ的清除[39]。本文提到的rs6656401，rs4266886，rs61822977是AD的易感基因，可增加AD患病的風(fēng)險(xiǎn)。

表2 AD免疫調(diào)節(jié)相關(guān)易感基因

3.內(nèi)吞作用相關(guān)基因

3.1 BIN1基因 BIN1基因?yàn)锳POE后最明顯的LOAD易感基因座，其編碼的橋聯(lián)整合蛋白1具有普遍表達(dá)性和組織特異性，包括腦中特異性同型(iso1)和普遍存在的較小同型(iso9)[40～42]。經(jīng)研究發(fā)現(xiàn)在AD患者的大腦中，iso1的水平顯著降低，而iso9的水平提高[41]。已知BIN1的功能包括調(diào)節(jié)膜曲率、介導(dǎo)網(wǎng)格蛋白內(nèi)吞作用和膜泡運(yùn)輸[41,12～18]。BIN1基因的多態(tài)性，一些會破壞BIN1接到的網(wǎng)格蛋白內(nèi)吞作用，降低APP的加工作用[43]，從而對LOAD起保護(hù)作用。相反一些破壞了對網(wǎng)格蛋白內(nèi)吞作用的抑制作用，就會增加其對LOAD的風(fēng)險(xiǎn)。本文中提到的rs6733839，rs12989701，rs744373為LOAD的易感基因。

3.2 CD2AP基因 CD2AP編碼CD2相關(guān)蛋白，這種支架蛋白參與內(nèi)吞作用和膜運(yùn)輸作用和動態(tài)肌動蛋白重塑作用。CD2AP在大腦的神經(jīng)元與毛細(xì)血管中有表達(dá)。在AD的果蠅模型中，發(fā)現(xiàn)果蠅的cindr為人類CD2AP直系同源物，也被認(rèn)為是介導(dǎo)Tau調(diào)節(jié)的疾病的機(jī)制[44]。研究發(fā)現(xiàn)CD2AP可影響體外的Aβ水平和Aβ42/Aβ40的比例，但對體內(nèi)的Aβ代謝影響甚微[45]。近期[46]研究顯示，神經(jīng)元的神經(jīng)突長度、復(fù)雜度、生成的錐形偽足數(shù)與CD2AP的表達(dá)相符。而在發(fā)散性AD患者外周血淋巴細(xì)胞(PBL)中檢測到CD2AP表達(dá)顯著降低，即可能CD2AP在全身參與了發(fā)散性AD。

3.3 PICALM基因 PICALM基因編碼參與網(wǎng)格蛋白介導(dǎo)的內(nèi)吞作用，其為細(xì)胞內(nèi)運(yùn)輸?shù)鞍踪|(zhì)、脂質(zhì)、生長因子和神經(jīng)遞質(zhì)的重要步驟。PICALM蛋白對于突觸前膜的神經(jīng)遞質(zhì)釋放不可或缺，對記憶形成和神經(jīng)元功能十分重要[47]。PICALM的缺陷減少了Aβ的清除和加速Aβ的病理學(xué)進(jìn)程，這對Aβ在腦內(nèi)的穩(wěn)態(tài)和清除的治療有影響[48]。PICALM水平也與磷酸化、自噬相關(guān)的蛋白水平相關(guān)，也與AD中的tau包涵體相關(guān)。文中提到的SNP rs3851179位于PICALM上游約90kb，保護(hù)性變體A與微血管系統(tǒng)中適度增加的PICALM表達(dá)相關(guān)，這可能有助于Aβ的清除，并可降低AD風(fēng)險(xiǎn)。此外，PICALM rs3851179 A等位基因與92～93歲的患者相比，具有更好的認(rèn)知能力，rs3851179 GA或AA基因型顯示出顯著的效應(yīng)與GG攜帶者相比，在藥物遺傳學(xué)測定過程中防止AD快速進(jìn)展[49]。

3.4 SLC242A基因GWAS 對于與AD相關(guān)的SLC24A4的功能知之甚少。SLC24A4可能參與神經(jīng)發(fā)育[50]。另外，SLC24A4基因位于RIN3基因旁邊，其與早期內(nèi)吞途徑中的BIN1有相互作用。

3.5 SORL1基因 遺傳和生物學(xué)證據(jù)表明，分揀蛋白相關(guān)受體1(SORL1)的紊亂功能與AD相關(guān)。作為AD的神經(jīng)病理學(xué)標(biāo)志，功能性SORL1降低腦中的淀粉樣蛋白β水平，從而降低神經(jīng)毒性淀粉樣蛋白β斑塊的負(fù)荷[59]。SORL1通過結(jié)合淀粉樣蛋白前體蛋白(APP)降低淀粉樣蛋白-β水平，防止其加工成淀粉樣蛋白-β，通過結(jié)合淀粉樣蛋白-β并將其引導(dǎo)至溶酶體降解[60]。對于SORL1，有趣的是，基因中常見和罕見的變體都能提高LOAD的風(fēng)險(xiǎn)。分子研究表明，SORL1的蛋白質(zhì)編碼區(qū)中的變體影響編碼蛋白的功能，即Sortilin相關(guān)受體，導(dǎo)致淀粉樣蛋白前體蛋白加工的改變，以及作為淀粉樣蛋白斑塊成分的淀粉樣β肽的下游分泌[61]。

表3 AD內(nèi)吞作用相關(guān)易感基因

4.神經(jīng)遞質(zhì)相關(guān)基因

4.1 APP基因 APP基因與AD高度相關(guān)，AD的特征在于淀粉樣蛋白斑，突觸損失和細(xì)胞死亡。由APP基因編碼的細(xì)胞表面受體和跨膜前體蛋白，經(jīng)β-分泌酶和γ-分泌酶水解產(chǎn)生的Aβ片段是阿爾茨海默病患者鬧鐘淀粉樣蛋白斑的蛋白質(zhì)基礎(chǔ)。Aβ是不同因素對AD的共同通路，也是AD發(fā)展的重要因素[51]。Aβ在正常人腦中經(jīng)分泌酶釋放到胞外區(qū)，此過程中Aβ將分裂成兩半，阻止Aβ的合成。若APP突變，涉及常染色體顯性阿爾茨海默病的產(chǎn)生。這是因?yàn)橛坞x的Aβ變長，經(jīng)聚集生成不可逆具神經(jīng)毒性的沉淀，導(dǎo)致生成淀粉樣蛋白斑進(jìn)而引發(fā)AD[52]。

4.2 PSEN1和PSEN2基因 PSEN1和PSEN2是γ-分泌酶復(fù)合物的重要元素，其在APP的蛋白水解切割中具有關(guān)鍵作用。在早老素基因中鑒定的大多數(shù)突變聚集在跨膜結(jié)構(gòu)域(TMD)中，并且它們通過APP處理導(dǎo)致淀粉樣蛋白生成肽Aβ1～42的過量產(chǎn)生[56]。與PSEN2和APP基因相比，PSEN1基因突變更為頻繁。迄今為止，在全球范圍內(nèi)已經(jīng)確定了超過216個(gè)人有突變，PSEN1基因影響了476個(gè)家庭。PSEN1突變的AD患者的臨床照片通常顯示非常早的發(fā)病年齡和快速的疾病過程。然而，根據(jù)皮質(zhì)區(qū)域病變的形態(tài)，確定了AD在遺傳學(xué)上與PSEN1相關(guān)，即使在同一家族中也可能表現(xiàn)出廣泛的表型變異性[57]。近來，焦點(diǎn)關(guān)注在小腦區(qū)域體積的損失與退行性皮層區(qū)域特異性互聯(lián)，尤其突出了小腦在AD相關(guān)神經(jīng)中的參與程度[58]。

4.3 PTK2B基因 PTK2B屬于FAK蛋白質(zhì)，已知其在細(xì)胞粘附途徑中直接相互作用[62]。PTK2B已被報(bào)道與整合素下游的CAS家族成員物理相互作用[63]。經(jīng)研究觀察得到蒼蠅，小鼠和人AD大腦中Tau與粘著斑基因PTK2B之間的強(qiáng)相互作用，共同表明PTK2B是AD中Tau病理學(xué)的重要早期標(biāo)記物和調(diào)節(jié)劑。Fak(PTK2B)作為Tau毒性調(diào)節(jié)劑。其中，粘著斑激酶Fak在眼睛和獨(dú)立的粘連相關(guān)性翼狀起泡分析中表現(xiàn)為強(qiáng)的Tau毒性抑制劑。因此，人Tau和PTK2B蛋白在體外生物化學(xué)相互作用，PTK2B與AD患者和轉(zhuǎn)基因Tau小鼠腦中進(jìn)行性病理分期的超磷酸化和低聚Tau共定位。這些數(shù)據(jù)表明PTK2B作為Tau毒性的早期標(biāo)記物和體內(nèi)調(diào)節(jié)劑[64]。

4.4 ZCWPW1基因 ZCWPW1是組蛋白修飾讀者，涉及表觀遺傳調(diào)控[71]。ZCWPW1作為GATS，PILRB和TRIM4的eQTL(表達(dá)數(shù)量性狀位點(diǎn))，并顯示影響RFX3和CTCF結(jié)合的指示[72]。此外，在一個(gè)大的LD區(qū)域，ZCWPW1區(qū)域中稱為NYAP1的候選基因可激活神經(jīng)元中的PI3K信號通路，從而抑制LOAD發(fā)生[73,74]。

表4 AD神經(jīng)遞質(zhì)相關(guān)易感基因

5.線粒體相關(guān)基因——TOMM40基因

TOMM40(外部線粒體膜轉(zhuǎn)移酶40)基因是位于19q13.2，其與APOE連鎖不平衡(LD)[65]。TOMM40編碼與Tom22，Tom7，Tom5和Tom6形成復(fù)合物的線粒體蛋白(Tom40)，并參與外線粒體膜的蛋白質(zhì)前體的整合[66]。此外，已經(jīng)描述了TOMM40與APOE，APP和Aβ的相互作用，促進(jìn)線粒體毒性和降低線粒體遷移率[67]。TOMM40，rs2075650中的單核苷酸多態(tài)性(SNPs)是APOE基因座周圍與AD密切相關(guān)的第二個(gè)標(biāo)記，已被證明是參與海馬完整性，杏仁核體積和情景記憶[68]。

表5 AD線粒體相關(guān)易感基因

6.其他與AD相關(guān)的易感基因

6.1 MTHFR基因 高血清同型半胱氨酸水平(Hcy)的升高與多種血管疾病和AD相關(guān)。Hcy可以通過幾種機(jī)制引起腦損傷，如糖尿病腎病A修復(fù)的損傷，β-淀粉樣蛋白肽生成的增強(qiáng)和神經(jīng)元對淀粉樣蛋白的敏感化[53,54]。已有一些機(jī)制的提出來說明Hcy導(dǎo)致AD：①Hcy可以誘導(dǎo)鈣流入和氧化應(yīng)激，產(chǎn)生游離氧自由基，加速糖尿病腎病A損傷并最終導(dǎo)致神經(jīng)元凋亡，②Hcy參與AD的病理生理學(xué)中的淀粉樣蛋白途徑參，③Hcy損害血管內(nèi)皮功能，刺激血管平滑肌增生，打破凝血和出血通路之間的平衡，并介導(dǎo)血栓形成。最終，這些副作用減少了對大腦的供血，加速了神經(jīng)細(xì)胞的凋亡[55]。

6.2 INPP5D、FERMT2基因 通過GWAS分析，得到了AD的易感基因，INPP5D和FERMT2[75]。這兩種基因在AD中的作用尚不清楚，但是這兩個(gè)基因改變了AD中的一直的途徑。INPP5D參與了免疫反應(yīng)，F(xiàn)ERMT2還參與了tau蛋白代謝[75]。這些基因出現(xiàn)在基因密集區(qū)，因此目前仍不清楚它們具體和哪些基因相關(guān)聯(lián)。

表6 其他與AD相關(guān)易感基因

AD是一種多基因多種因素共同影響的老年疾病，而AD給家庭和社會帶了諸多的壓力，這也致使探明AD形成機(jī)制并確定合理的治療方案尤為重要。發(fā)現(xiàn)和識別新的易感基因，有助于為了解AD的形成機(jī)制及對AD的防治提供新的方向。隨著全基因組關(guān)聯(lián)分析和第二代測序的發(fā)展，將有越來越多的易感基因添加到已知的隊(duì)列中，一些待發(fā)現(xiàn)的相關(guān)通路途徑和細(xì)胞機(jī)制也將被識別鑒定。

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Advances in genetics of Alzheimer’s disease

(GAOShan1,2,CHENChao2,LIZhipeng2,YANGZe1.1.InstituteofGeriatrics,MinistryofHealth,BeijingHospital,Beijing100730.2.BeijingNormalUniversity(Zhuhai),Zhuhai518000,China.)

Alzheimer’s disease (AD) is a common central neurodegenerative disease.It is generally believed that the occurrence of AD is the result of the interaction among genetic,environmental,metabolic and other factors.The AD research reach level of molecular genetics and genomics since the end of the 20th century have gradually revealed some genes implicated in AD.Here we review the AD risk genes (ABCA7,APOE,CLU,ESR2,CR1,INPP5D,BIN1,CD2AP,PICALM,SLC242A,APP,MTHFR,PSEN1,PSEN2,SORL1,PTK2B,TOMM40,PTGS2,ZCWPW1,FERMT2 ) for AD since 2016.

Alzheimer’s disease, Risk gene

1.北京醫(yī)院 北京老年醫(yī)學(xué)研究所，100730 2.北京師范大學(xué)珠海分校 518000

國家自然科學(xué)基金(81460203，8321120527，81370265，8147108,81400710)，衛(wèi)生部公益性研究基金(201192008)和國家科技部十二五支撐計(jì)劃(2012BAI10B01),北京市科技新星計(jì)劃(Z12133002512058)。

10.3969/j.issn.1672-4860.2017.04.006

2017-7-15

※Correspondingauthor:ChenChao,YangZe.