P301S突變tau轉(zhuǎn)基因動(dòng)物模型及其應(yīng)用

馬登磊, 張 蘭

(首都醫(yī)科大學(xué)宣武醫(yī)院藥物研究室, 神經(jīng)變性病教育部重點(diǎn)實(shí)驗(yàn)室,北京市神經(jīng)藥物工程研究中心, 北京 100053)

·綜 述·

P301S突變tau轉(zhuǎn)基因動(dòng)物模型及其應(yīng)用

馬登磊, 張 蘭

(首都醫(yī)科大學(xué)宣武醫(yī)院藥物研究室, 神經(jīng)變性病教育部重點(diǎn)實(shí)驗(yàn)室,北京市神經(jīng)藥物工程研究中心, 北京 100053)

微管相關(guān)蛋白tau在細(xì)胞內(nèi)形成的神經(jīng)纖維纏結(jié)是包括阿爾茨海默病(AD)、連鎖于17號(hào)染色體伴帕金森綜合征的額顳葉癡呆(FTDP-17)等在內(nèi)的多種tau蛋白病(tauopathies)的主要病理表現(xiàn)之一。國(guó)內(nèi)外學(xué)者在FTDP-17患者中發(fā)現(xiàn)了tau基因存在多個(gè)位點(diǎn)的突變，并以此為基礎(chǔ)制作了多種tau轉(zhuǎn)基因動(dòng)物模型。其中P301S突變tau蛋白轉(zhuǎn)基因小鼠模型在國(guó)內(nèi)外的tau相關(guān)疾病研究中得到了廣泛應(yīng)用。本文綜述了P301S突變tau轉(zhuǎn)基因小鼠的病理表現(xiàn)及應(yīng)用的新進(jìn)展。

P301S突變; tau蛋白; 轉(zhuǎn)基因小鼠; 阿爾茨海默病; tau蛋白病

阿爾茨海默病(Alzheimer’s disease, AD)的兩個(gè)主要病理特征為由β-淀粉樣蛋白(β-amyloid, Aβ)沉積而形成的老年斑和由過度磷酸化tau蛋白在細(xì)胞內(nèi)聚集形成的神經(jīng)原纖維纏結(jié)(neurofibrillary tangles,NFTs)。研究表明, AD患者腦內(nèi)NFTs與神經(jīng)元死亡和認(rèn)知功能降低具有更高的相關(guān)性[1,2], 因此以tau蛋白為靶點(diǎn)的藥物研究獲得了越來越多的關(guān)注[3]。目前國(guó)內(nèi)外學(xué)者已經(jīng)建立了多種tau蛋白相關(guān)動(dòng)物模型[4,5]。其中, tau蛋白轉(zhuǎn)基因動(dòng)物模型可以模擬AD及其他tau蛋白病(tauopathy)的一些疾病特征, 例如tau蛋白的磷酸化和病理性沉積、神經(jīng)元死亡、認(rèn)知功能障礙等[4]。本文對(duì)應(yīng)用比較廣泛的P301S突變tau蛋白轉(zhuǎn)基因小鼠模型做一綜述, 說明模型的主要病理表現(xiàn)及其在藥理學(xué)研究中的應(yīng)用。

1 微管相關(guān)蛋白tau

1.1 結(jié)構(gòu)和功能

Tau蛋白是微管結(jié)合蛋白家族中的一員。在正常的神經(jīng)元中，tau蛋白主要富集于神經(jīng)元軸突內(nèi)，主要生理功能是與微管結(jié)合，調(diào)節(jié)微管的組裝與解聚，維持微管的穩(wěn)定性[6]; tau蛋白還輔助神經(jīng)元軸突的運(yùn)輸功能，參與維持細(xì)胞形態(tài)、信號(hào)傳遞等生理過程[7]; 同時(shí)還具有促進(jìn)軸突生長(zhǎng)發(fā)育和神經(jīng)元極性的作用等[8]。在異常情況下，tau蛋白的高度磷酸化和聚集可引起多種tau蛋白病，包括阿爾茨海默病、連鎖于17號(hào)染色體tau突變伴帕金森綜合征的額顳葉癡呆(frontotemporal dementia with Parkinsonism linked to tau mutations on chromosome 17, FTDP-17)、Pick病、進(jìn)行性核上性麻痹、皮質(zhì)基底節(jié)變性等。

1.2 Tau蛋白的磷酸化和聚集

在tau蛋白病中，tau蛋白會(huì)發(fā)生多種病理變化，例如磷酸化、構(gòu)象改變、寡聚體以及tau蛋白的聚集，其中tau蛋白的過度磷酸化為主要的病理表現(xiàn)之一。研究結(jié)果顯示，在AD及其他tau蛋白病的病理變化中均含有高度磷酸化的tau蛋白[9]。過度磷酸化的tau蛋白從微管上解聚，不再發(fā)揮正常的生理功能，并聚集形成神經(jīng)原纖維纏結(jié)，進(jìn)而影響軸突的正常轉(zhuǎn)運(yùn)，引起神經(jīng)元變性和功能損傷[10]。在AD患者腦中，游離于細(xì)胞質(zhì)中的磷酸化tau蛋白(AD P-tau)不僅不能與微管蛋白結(jié)合發(fā)揮正常的生理功能，反而會(huì)抑制微管的組裝[11]。

1.3 Tau的基因突變

微管相關(guān)蛋白tau(microtubule-associated protein tau，MAPT)的基因突變最早發(fā)現(xiàn)于FTDP-17患病家系中[12]。目前已經(jīng)在17號(hào)染色體多個(gè)位點(diǎn)上發(fā)現(xiàn)了Tau基因突變，包括R5L、K257T、I260V、G272V、Δ K280、P301L、P301S、Q336R、V337M、R406W等[13]。其中, P301S突變位于外顯子10，編碼全長(zhǎng)tau第301位氨基酸的三個(gè)堿基中第一個(gè)C錯(cuò)義突變?yōu)門，導(dǎo)致該位置的脯氨酸(Pro)變?yōu)榻z氨酸(Ser)。P301S突變位點(diǎn)位于MAPT基因片段的微管結(jié)合區(qū)，影響tau蛋白與微管的結(jié)合，促進(jìn)tau纖維絲的形成[14,15]; 在體內(nèi)和體外實(shí)驗(yàn)中均顯示該突變會(huì)促進(jìn)磷酸化tau蛋白聚集成細(xì)絲或神經(jīng)原纖維纏結(jié)[16,17]。

2 PS19轉(zhuǎn)基因小鼠

很多FTDP-17突變tau通過單轉(zhuǎn)或者多轉(zhuǎn)的方式, 建立了相應(yīng)的過表達(dá)轉(zhuǎn)基因動(dòng)物模型。其中，過表達(dá)P301S突變tau蛋白的轉(zhuǎn)基因小鼠(PS19轉(zhuǎn)基因小鼠)具有很明顯的tau蛋白相關(guān)病理表現(xiàn)和認(rèn)知功能障礙，因此得到較為廣泛的應(yīng)用。

2.1 PS19轉(zhuǎn)基因小鼠的病理表現(xiàn)

Yoshiyama等[18]構(gòu)建了以鼠PrnP為啟動(dòng)子過表達(dá)P301S突變的人1N4R tau蛋白的轉(zhuǎn)基因小鼠模型，即PS19轉(zhuǎn)基因小鼠。PS19轉(zhuǎn)基因小鼠在皮層和海馬等部位過表達(dá)3～5倍的人源P301S突變tau蛋白。在PS19轉(zhuǎn)基因小鼠3月齡時(shí)，突變tau蛋白與微管結(jié)合的能力降低，小鼠腦內(nèi)神經(jīng)元開始出現(xiàn)因高度磷酸化形成的不可溶tau蛋白。5月齡，PS19轉(zhuǎn)基因小鼠新皮層、海馬和杏仁核出現(xiàn)tau蛋白聚集形成的雙股螺旋細(xì)絲(paired helical filaments,PHFs)和NFTs[18]。另外有研究[19]顯示, PS19轉(zhuǎn)基因小鼠腦脊液中tau蛋白的濃度為內(nèi)源性鼠tau的5倍,與腦內(nèi)過表達(dá)tau的量是一致的; 而隨著月齡增長(zhǎng)及tau蛋白聚集的增加，小鼠腦脊液中tau單倍體的含量減少，提示細(xì)胞外tau蛋白與聚集態(tài)tau蛋白存在一個(gè)平衡狀態(tài)。除了tau蛋白相關(guān)病變外，PS19轉(zhuǎn)基因小鼠還會(huì)出現(xiàn)小膠質(zhì)細(xì)胞激活等神經(jīng)炎癥反應(yīng)，并進(jìn)一步導(dǎo)致皮層和海馬體積縮小和神經(jīng)元的丟失[18,20]。同時(shí)在tau病變的早期，PS19轉(zhuǎn)基因小鼠出現(xiàn)氧化應(yīng)激和線粒體紊亂，并通過激活促腎上腺皮質(zhì)激素釋放因子受體通路進(jìn)一步加劇tau蛋白病變和認(rèn)知障礙[21,22]。PS19轉(zhuǎn)基因小鼠還出現(xiàn)突觸可塑性的降低以及突觸丟失，并影響谷氨酸受體進(jìn)而損傷突觸功能[23]。另有研究[24]表明, P301S突變可以引起轉(zhuǎn)基因小鼠腦組織染色體發(fā)生非整倍體變化，這可能也是促進(jìn)神經(jīng)退行性病變的機(jī)制之一。

2.2 PS19轉(zhuǎn)基因小鼠的行為學(xué)變化

6月齡PS19轉(zhuǎn)基因小鼠在Morris水迷宮、Barnes迷宮和Y迷宮試驗(yàn)中均出現(xiàn)空間認(rèn)知障礙，在三室社交試驗(yàn)中顯示社交記憶障礙，物體識(shí)別試驗(yàn)中表現(xiàn)出記憶障礙，前脈沖抑制試驗(yàn)中顯示信息處理和感覺運(yùn)動(dòng)閾異常，曠場(chǎng)試驗(yàn)中顯示高活動(dòng)性癥狀，而運(yùn)動(dòng)能力和協(xié)調(diào)能力未發(fā)生明顯變化；但老年P(guān)S19轉(zhuǎn)基因小鼠會(huì)出現(xiàn)后肢癱瘓等運(yùn)動(dòng)癥狀[18,21,25]。以上行為學(xué)試驗(yàn)結(jié)果表明，PS19轉(zhuǎn)基因小鼠出現(xiàn)了明顯的認(rèn)知能力障礙和精神異常; 在青年期無明顯的運(yùn)動(dòng)異常，但在老年期出現(xiàn)明顯的運(yùn)動(dòng)障礙。由于該小鼠品系表現(xiàn)出明顯的包括tau病變?cè)趦?nèi)的多個(gè)病理表現(xiàn)以及行為異常，因此近些年來廣泛用于tau蛋白病和神經(jīng)退行性疾病的發(fā)病機(jī)制研究以及藥物研究中。

3 PS19轉(zhuǎn)基因小鼠的應(yīng)用

3.1 在病理機(jī)制研究中的應(yīng)用

作為一個(gè)具有明顯病理表現(xiàn)的tau蛋白轉(zhuǎn)基因模型，PS19轉(zhuǎn)基因小鼠可以用于研究tau蛋白相關(guān)的病理機(jī)制，例如tau seeding，tau的乙酰化等。應(yīng)用PS19轉(zhuǎn)基因小鼠研究發(fā)現(xiàn)P301S突變tau蛋白在體內(nèi)引起的tau seeding可以預(yù)測(cè)tau蛋白病變的發(fā)展程度[26]; 另有研究[22,27,28]在幼年P(guān)S19轉(zhuǎn)基因小鼠腦內(nèi)注射AD患者的tau蛋白或合成的tau纖維絲之后，可以誘導(dǎo)和促進(jìn)病理性tau蛋白在腦內(nèi)的分散和傳播，加重疾病進(jìn)程，從而探明腦內(nèi)病理性tau蛋白擴(kuò)散的方式和機(jī)制。在PS19轉(zhuǎn)基因小鼠模型中，tau的乙酰化可以通過抑制tau蛋白與微管的結(jié)合以及促進(jìn)tau蛋白聚集從而加速tau的病理變化，而應(yīng)用相應(yīng)抗體抑制tau蛋白的乙酰化可以減輕tau蛋白高度磷酸化等病變[29,30]。另外，PS19轉(zhuǎn)基因小鼠作為疾病模型還應(yīng)用于正電子發(fā)射斷層掃描(positron emission tomography，PET)診斷以及生物標(biāo)志物的研究中[31,32]。

3.2 在藥理學(xué)研究中的應(yīng)用

目前，以PS19轉(zhuǎn)基因小鼠為疾病模型進(jìn)行了諸多方面的藥物研發(fā)。包括:

3.2.1 膽堿酯酶抑制劑 有研究[33]報(bào)道膽堿酯酶抑制劑多奈哌齊可以增高PS19轉(zhuǎn)基因小鼠的存活率，降低tau蛋白異常磷酸化以及NFTs等病理變化，改善突觸和神經(jīng)元的丟失和形態(tài); 其機(jī)制可能與多奈哌齊抑制MAPK和JNK通路的激活以及膠質(zhì)細(xì)胞的激活、發(fā)揮抗炎作用有關(guān)。而給予抗膽堿類藥物可以加重PS19轉(zhuǎn)基因小鼠的病理表現(xiàn)[34]。

3.2.2 Tau蛋白免疫療法 抗tau抗體側(cè)腦室注射或腹腔注射到6月齡PS19轉(zhuǎn)基因小鼠中, 3個(gè)月后可以降低tau蛋白的異常磷酸化, 減少tau的聚集和神經(jīng)原纖維纏結(jié), 改善條件恐懼認(rèn)知障礙和感覺運(yùn)動(dòng)障礙, 其機(jī)制可能與抗體阻斷病理性tau的傳播, 促進(jìn)小膠質(zhì)細(xì)胞對(duì)病理性tau的消除有關(guān)[35,36]。給予PS19轉(zhuǎn)基因小鼠抗磷酸化tau蛋白抗體, 可以降低腦內(nèi)和腦脊液中磷酸化tau蛋白的含量, 改善物體識(shí)別試驗(yàn)中的認(rèn)知障礙[37]。以tau蛋白雙磷酸化位點(diǎn)的肽段作為疫苗引發(fā)PS19轉(zhuǎn)基因小鼠的主動(dòng)免疫, 可降低tau蛋白病變, 改善小鼠的行為障礙和存活率[38]。

3.2.3 降低tau蛋白磷酸化和聚集 苯扎貝特作為過氧化物酶體增殖劑激活受體(peroxisome proliferatorsactivated receptors, PPARs)激動(dòng)劑，給藥后可以降低PS19轉(zhuǎn)基因小鼠腦內(nèi)tau蛋白磷酸化和聚集，抑制神經(jīng)炎癥，改善脂類代謝和氧化應(yīng)激，并改善小鼠的行為障礙[39]。新藥anle138b可以與PS19轉(zhuǎn)基因小鼠體內(nèi)聚集的tau蛋白結(jié)合并抑制tau蛋白的聚集，保護(hù)神經(jīng)元和突觸，進(jìn)而改善小鼠行為學(xué)表現(xiàn)和存活率[40]。雷帕霉素作為mTOR通路抑制劑，可以降低PS19轉(zhuǎn)基因小鼠tau高度磷酸化，改善突觸和神經(jīng)元丟失，并改善軸突功能和認(rèn)知行為障礙，其機(jī)制可能與雷帕霉素抑制糖原合成酶激酶3β(glycogen synthase kinase-3β，GSK-3β)的活性以及增強(qiáng)自噬功能有關(guān)[41]。坦西莫司可以降低PS19轉(zhuǎn)基因小鼠體內(nèi)tau蛋白磷酸化水平，改善空間認(rèn)知障礙，其機(jī)制可能與抑制GSK-3β的活性和激活細(xì)胞自噬有關(guān)[42]。

3.2.4 Tau蛋白的清除 轉(zhuǎn)錄因子EB(TFEB)作為自噬溶酶體途徑重要的調(diào)節(jié)因子，在PS19轉(zhuǎn)基因小鼠中過表達(dá)可以減少tau蛋白聚集形成的PHF和溶酶體碎片，保護(hù)神經(jīng)元和認(rèn)知功能[43]。在PS19轉(zhuǎn)基因小鼠側(cè)腦室注射人tau的反義寡核苷酸ASOs, 可以降低tau的mRNA和蛋白的表達(dá)水平，減輕tau蛋白病變，防止海馬體積萎縮和神經(jīng)元死亡，改善行為障礙[44]。

3.2.5 微管穩(wěn)定劑 埃博霉素D給予PS19轉(zhuǎn)基因小鼠治療3個(gè)月, 可以減輕腦內(nèi)tau病變，減少神經(jīng)元和突觸丟失, 改善突觸功能和認(rèn)知功能，其機(jī)制主要是藥物維持了微管的穩(wěn)定性，進(jìn)而保護(hù)了軸突[45,46]。煙酰胺-核苷酸腺苷轉(zhuǎn)移酶1(nicotinamide nucleotide adenylyltransferase 1，Nmnat1)作為軸突退化抑制劑，在PS19轉(zhuǎn)基因小鼠過表達(dá)可以降低不溶性tau蛋白的含量，保護(hù)神經(jīng)元的功能[47]。

3.2.6 抑制神經(jīng)炎癥 通過促進(jìn)髓系細(xì)胞2中表達(dá)觸發(fā)受體(triggering receptor expressed on myeloid cells 2，TREM2)基因的表達(dá)，可以改善PS19轉(zhuǎn)基因小鼠的認(rèn)知障礙，降低tau蛋白磷酸化和神經(jīng)元丟失等神經(jīng)病理表現(xiàn); 主要機(jī)制為TREM2改變了小膠質(zhì)細(xì)胞的表型，降低了神經(jīng)炎癥和tau蛋白相關(guān)激酶的活性[48,49]。

3.2.7 改善代謝 輔酶Q和亞甲藍(lán)可以通過改善線粒體代謝或抑制氧化應(yīng)激，進(jìn)而改善PS19轉(zhuǎn)基因小鼠的tau蛋白病變和行為障礙[50,51]。另外也有研究[52,53]顯示，運(yùn)動(dòng)鍛煉可以改善PS19或肥胖PS19轉(zhuǎn)基因小鼠的tau相關(guān)病變以及行為學(xué)表現(xiàn)。

3.2.8 其他藥物或藥物靶點(diǎn) 存在于溶酶體的天冬酰胺內(nèi)肽酶(asparagine endopeptidase，AEP)在老化過程中被激活并裂解tau蛋白，使后者喪失微管裝配功能，誘導(dǎo)tau蛋白聚集并引發(fā)神經(jīng)退行性病變;而在PS19轉(zhuǎn)基因小鼠中敲除AEP的編碼基因，可以顯著降低tau蛋白的過度磷酸化和突觸損失，改善突觸功能和認(rèn)知能力[54]。治療糖尿病的藥物二甲雙胍可以降低PS19轉(zhuǎn)基因小鼠的tau蛋白磷酸化，但是同時(shí)也會(huì)促進(jìn)tau蛋白的聚集，加重小鼠的運(yùn)動(dòng)障礙和高活動(dòng)性等行為異常[55]。

4 其他P301S突變tau轉(zhuǎn)基因動(dòng)物

除了PS19轉(zhuǎn)基因小鼠外, Allen等[56]以鼠Thy1.2為啟動(dòng)子，構(gòu)建了表達(dá)P301S突變?nèi)嗽?N4R tau蛋白的轉(zhuǎn)基因小鼠，該小鼠tau蛋白的表達(dá)量約為野生型的兩倍。該轉(zhuǎn)基因小鼠在5～6月齡時(shí)，神經(jīng)元內(nèi)出現(xiàn)高度磷酸化不溶性tau蛋白，隨后出現(xiàn)NFTs和Pick小體樣內(nèi)涵體，以及扭曲狀tau蛋白纖絲。此外，該轉(zhuǎn)基因小鼠還出現(xiàn)小膠質(zhì)細(xì)胞的激活和神經(jīng)炎癥[57]，同時(shí)也會(huì)出現(xiàn)脊髓運(yùn)動(dòng)神經(jīng)元的丟失并引發(fā)肌力降低等運(yùn)動(dòng)癥狀[58]。P301S突變tau蛋白除了用于構(gòu)建單轉(zhuǎn)基因小鼠外，還可與其他基因一起構(gòu)建雙轉(zhuǎn)基因小鼠模型，從而獲得多種表型和病理改變[59]。

5 結(jié)語

與野生型tau蛋白相比，P301S突變tau蛋白更容易發(fā)生聚集; 因此P301S轉(zhuǎn)基因小鼠由于P301S突變tau蛋白的過表達(dá)引起的明顯的tau病理改變，進(jìn)而可以很好地模擬tau蛋白病(tauopathy)，例如AD等。因此，該模型可以用于研究AD等tau蛋白相關(guān)疾病的發(fā)病機(jī)制和靶點(diǎn)藥物的開發(fā)。但是PS19轉(zhuǎn)基因小鼠在9～12月齡開始出現(xiàn)后肢等部位的萎縮，進(jìn)而影響小鼠的運(yùn)動(dòng)功能，最終引起小鼠的死亡，因此在應(yīng)用該小鼠模型時(shí)建議使用較早月齡的小鼠。另外，該模型只是過表達(dá)一種突變的tau蛋白，而人的tau蛋白有多種異構(gòu)體，因此該模型不能完全模擬疾病模型中tau蛋白病變過程。同時(shí)，AD具有多種病理表現(xiàn)，tau轉(zhuǎn)基因小鼠模型并不能完全模擬AD等復(fù)雜疾病的發(fā)病機(jī)制。盡管如此，P301S突變tau轉(zhuǎn)基因小鼠模型的建立加深了對(duì)于AD等tau蛋白病的分子機(jī)制的認(rèn)識(shí)，尤其是tau蛋白病變與神經(jīng)退行性病變的關(guān)系。同時(shí)，這些模型也廣泛應(yīng)用于以tau蛋白為靶點(diǎn)的藥理學(xué)研究中，對(duì)于AD及其他tau蛋白病的新藥研發(fā)具有重要的意義。

[1] Nagy Z, Esiri MM, Jobst KA, et al. Relative roles of plaques and tangles in the dementia of Alzheimer’s disease: correlations using three sets of neuropathological criteria[J].Dementia, 1995, 6(1):21-31.

[2] Murray ME, Lowe VJ, Graff-Radford NR, et al. Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum[J].Brain, 2015, 138(Pt 5):1370-1381.

[3] Gong CX, Grundke-Iqbal I, Iqbal K. Targeting tau protein in Alzheimer’s disease[J]. Drugs Aging, 2010, 27(5):351-365.

[4] Dujardin S, Colin M, Bué e L. Invited review: Animal models of tauopathies and their implications for research/translation into the clinic[J]. Neuropathol Appl Neurobiol, 2015, 41(1):59-80.

[5] Noble W, Hanger DP, Gallo JM. Transgenic mouse models of tauopathy in drug discovery[J]. CNS Neurol Disord Drug Targets, 2010, 9(4):403-428.

[6] Weingarten MD, Lockwood AH, Hwo SY, et al. A protein factor essential for microtubule assembly[J]. Proc Natl Acad Sci U S A, 1975, 72(5):1858-1862.

[7] Dixit R, Ross JL, Goldman YE, et al. Differential regulation of dynein and kinesin motor proteins by tau [J]. Science,2008, 319(5866):1086-1089.

[8] Liu CW, Lee G, Jay DG. Tau is required for neurite outgrowth and growth cone motility of chick sensory neurons [J]. Cell Motil Cytoskeleton, 1999, 43(3):232-242.

[9] Iqbal K, Liu F, Gong CX, et al. Mechanisms of tau-induced neurodegeneration [J]. Acta Neuropathol, 2009, 118(1):53-69.

[10] Iqbal K, Liu F, Gong CX. Tau and neurodegenerative disease:the story so far [J]. Nat Rev Neurol, 2016, 12(1):15-27.

[11] Li B, Chohan MO, Grundke-Iqbal I, et al. Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau [J]. Acta Neuropathol, 2007, 113(5):501-511.

[12] Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17 [J]. Nature, 1998, 393(6686):702-705.

[13] Stenson PD, Mort M, Ball EV, et al. The human gene mutation database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine [J]. Hum Genet, 2014, 133(1):1-9.

[14] Hong M, Zhukareva V, Vogelsberg-Ragaglia V, et al. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17 [J]. Science, 1998, 282(5395): 1914-1917.

[15] Chang E, Kim S, Yin H, et al. Pathogenicmissense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps [J]. J Neurochem,2008, 107(4):1113-1123.

[16] Alonso AD, Mederlyova A, Novak M, et al. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations [J]. J Biol Chem, 2004, 279(33):34873-34881.

[17] Ludvigson AE, Luebke JI, Lewis J, et al. Structural abnormalities in the cortex of the rTg4510 mouse model of tauopathy:a light and electron microscopy study [J]. Brain Struct Funct,2011, 216(1):31-42.

[18] Yoshiyama Y, Higuchi M, Zhang B, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model [J]. Neuron, 2007, 53(3):337-351.

[19] Yamada K, Cirrito JR, Stewart FR, et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice [J]. J Neurosci,2011, 31(37):13110-13117.

[20] López-González I, Aso E, Carmona M, et al. Neuroinflammatory gene regulation, mitochondrial function, oxidative stress, and brain lipid modifications with disease progression in tau P301S transgenic mice as a model of frontotemporal lobar degeneration-tau [J]. J Neuropathol Exp Neurol,2015, 74(10):975-999.

[21] Dumont M, Stack C, Elipenahli C, et al. Behavioral deficit,oxidative stress, and mitochondrial dysfunction precede tau pathology in P301S transgenic mice [J]. FASEB J, 2011, 25(11):4063-4072.

[22] Boluda S, Iba M, Zhang B, et al. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer's disease or corticobasal degeneration brains [J].Acta Neuropathol, 2015, 129(2):221-237.

[23] Crescenzi R, DeBrosse C, Nanga RP, et al. In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy [J]. Neuroimage, 2014, 101:185-192.

[24] Rossi G, Conconi D, Panzeri E, et al. Mutations in MAPT give rise to aneuploidy in animal models of tauopathy [J].Neurogenetics, 2014, 15(1):31-40.

[25] Takeuchi H, Iba M, Inoue H, et al. P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating[J]. PLoS One, 2011, 6(6):e21050.

[26] Holmes BB, Furman JL, Mahan TE, et al. Proteopathic tau seeding predicts tauopathy in vivo [J]. Proc Natl Acad Sci USA, 2014, 111(41):E4376-4385.

[27] Iba M, Guo JL, McBride JD, et al. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy [J]. J Neurosci, 2013,33(3):1024-1037.

[28] Kaufman SK, Sanders DW, Thomas TL, et al. Tau prion strains dictate patterns of cell pathology, progression rate,and regional vulnerability in vivo [J]. Neuron, 2016, 92(4):796-812.

[29] Cohen TJ, Guo JL, Hurtado DE, et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation [J]. Nat Commun, 2011, 2:252.

[30] Min SW, Cho SH, Zhou Y, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy [J]. Neuron,2010, 67(6):953-966.

[31] Maeda J, Zhang MR, Okauchi T, et al. In vivo positron emission tomographic imaging of glial responses to amyloidbeta and tau pathologies in mouse models of Alzheimer’s disease and related disorders[J]. J Neurosci, 2011, 31(12):4720-4730.

[32] Ji B, Maeda J, Sawada M, et al. Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies [J]. J Neurosci, 2008,28(47):12255-12267.

[33] Yoshiyama Y, Kojima A, Ishikawa C, et al. Anti-inflammatory action of donepezil ameliorates tau pathology, synaptic loss,and neurodegeneration in a tauopathy mouse model [J]. J Alzheimers Dis, 2010, 22(1):295-306.

[34] Yoshiyama Y, Kojima A, Itoh K, et al. Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model [J]. Neurobiol Dis,2012, 45(1):329-336.

[35] Yanamandra K, Kfoury N, Jiang H, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo [J]. Neuron, 2013,80(2):402-414.

[36] Yanamandra K, Jiang H, Mahan TE, et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy [J]. Ann Clin Transl Neurol, 2015, 2(3):278-288.

[37] Sankaranarayanan S, Barten DM, Vana L, et al. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models [J]. PLoS One, 2015, 10(5):e0125614.

[38] Richter M, Mewes A, Fritsch M, et al. Doubly phosphorylated peptide vaccines to protect transgenic P301S mice against Alzheimer's disease like tau aggregation [J]. Vaccines(Basel),2014, 2(3):601-623.

[39] Dumont M, Stack C, Elipenahli C, et al. Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice [J]. Hum Mol Genet, 2012, 21(23):5091-5105.

[40] Wagner J, Krauss S, Shi S, et al. Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies [J]. Acta Neuropathol, 2015, 130(5):619-631.

[41] Caccamo A, Magrì A, Medina DX, et al. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies [J]. Aging Cell,2013, 12(3):370-380.

[42] Jiang T, Yu JT, Zhu XC, et al. Temsirolimus attenuates tauopathy in vitro and in vivo by targeting tau hyperphosphorylation and autophagic clearance [J]. Neuropharmacology,2014, 85:121-130.

[43] Wang H, Wang R, Carrera I, et al. TFEB overexpression in the P301S model of tauopathy mitigates increased PHF1 levels and lipofuscin puncta and rescues memory deficits [J]. eNeuro,2016, 3(2):1-18.

[44] DeVos SL, Miller RL, Schoch KM, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy [J]. Sci Transl Med,2017, 9(374):1-14.

[45] Brunden KR, Zhang B, Carroll J, et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy [J]. J Neurosci, 2010,30(41):13861-13866.

[46] Zhang B, Carroll J, Trojanowski JQ, et al. The microtubulestabilizing agent, epothilone D, reduces axonal dysfunction,neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice[J]. J Neurosci, 2012, 32(11):3601-3611.

[47] Musiek ES, Xiong DD, Patel T, et al. Nmnat1 protects neuronal function without altering phospho-tau pathology in a mouse model of tauopathy [J]. Ann Clin Transl Neurol,2016, 3(6):434-442.

[48] Jiang T, Tan L, Zhu XC, et al. Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice [J]. Neurobiol Aging,2015, 36(12):3176-3186.

[49] Jiang T, Zhang YD, Chen Q, et al. TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice [J]. Neuropharmacology, 2016, 105:196-206.

[50] Elipenahli C, Stack C, Jainuddin S, et al. Behavioral improvement after chronic administration of coenzyme Q10 in P301S transgenic mice [J]. J Alzheimers Dis, 2012, 28(1):173-182.

[51] Stack C, Jainuddin S, Elipenahli C, et al. Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity [J]. Hum Mol Genet, 2014, 23(14):3716-3732.

[52] Ohia-Nwoko O, Montazari S, Lau YS, et al. Long-term treadmill exercise attenuates tau pathology in P301S tau transgenic mice [J]. Mol Neurodegener, 2014, 9:54.

[53] Koga S, Kojima A, Ishikawa C, et al. Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model:implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression [J]. Neurobiol Dis, 2014,71:180-192.

[54] Zhang Z, Song M, Liu X, et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease [J]. Nat Med, 2014, 20(11):1254-1262.

[55] Barini E, Antico O, Zhao Y, et al. Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy [J]. Mol Neurodegener, 2016, 11:16.

[56] Allen B,Ingram E, Takao M, et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein [J]. J Neurosci, 2002, 22(21):9340-9351.

[57] Bellucci A, Westwood AJ, Ingram E, et al. Induction of inflammatory mediators andmicroglial activation in mice transgenic for mutant human P301Stau protein [J]. Am J Pathol, 2004, 165(5):1643-1652.

[58] Scattoni ML, Gasparini L, Alleva E, et al. Early behavioural markers of disease in P301S tau transgenic mice [J]. Behav Brain Res, 2010, 208(1):250-257.

[59] Rosenmann H, Grigoriadis N, Eldar-Levy H, et al. A noveltransgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics[J]. Exp Neurol, 2008, 212(1):71-84.

P301S Mutant Tau Transgenic Mouse and Their Applications

MA Deng-lei, ZHANG Lan
(Department of Pharmacology, Xuanwu Hospital of Capital Medical University;Key Laboratory for Neurodegenerative Diseases of Ministry of Education;Beijing Engineering Research Center for Nerve System Drugs, Beijing 100053, China)

Microtubule associated protein tau is the major component of the intracellular filamentous deposits of several tauopathies, including Alzheimer’s disease, frontotemporal dementia with Parkinsonism linked to tau mutations on chromosome 17(FTDP-17) and so on. Mutations in Tau as the cause of FTDP-17 have been identified in recent years. And transgenic animal models based on tau mutations have been established. Among these models, P301S transgenic mouse has been widely used in the research on tauopathies. This article reviews the research progress in pathogenic manifestations of P301S mutant tau transgenic mice and their applications.

P301S mutation; Tau protein; Transgenic mouse; Alzheimer’s disease; Tauopathy

Q95-33

A

1674-5817(2017)06-0491-06

10.3969/j.issn.1674-5817.2017.06.015

2017-08-14

國(guó)家自然科學(xué)基金項(xiàng)目(No. 81473373), 國(guó)家重大新藥創(chuàng)制科技重大專項(xiàng)(No. 2015ZX09101016001),北京市教委新醫(yī)藥學(xué)科群項(xiàng)目(No. XK100270569),北京市高層次衛(wèi)生技術(shù)人才計(jì)劃(No. 2014-2-014)

馬登磊(1988-), 男, 博士研究生, 研究方向: 神經(jīng)藥理學(xué)。E-mail: ma_denglei@126.com

張 蘭, 教授, 研究方向: 神經(jīng)藥理學(xué)。E-mail: lanizhg@126.com