Tau的病理性修飾與新生兒缺氧缺血性腦損傷*

肖 婕 ， 李 凡

(昆明醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院病理學(xué)與病理生理學(xué)系，云南 昆明 650500)

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·綜 述·

Tau的病理性修飾與新生兒缺氧缺血性腦損傷*

肖 婕 ， 李 凡△

(昆明醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院病理學(xué)與病理生理學(xué)系，云南 昆明 650500)

Tau是腦內(nèi)含量最多的微管相關(guān)蛋白(microtubule-associated proteins, MAPs)，其病理性改變與多種中樞神經(jīng)系統(tǒng)疾病密切相關(guān)。

1 Tau的生理功能

Tau在神經(jīng)細(xì)胞的軸突廣泛表達(dá)，主要起促進(jìn)微管(microtubulin, MT)形成和穩(wěn)定MT的作用，并參與細(xì)胞內(nèi)物質(zhì)運(yùn)輸、有絲分裂、神經(jīng)遞質(zhì)和信號(hào)傳遞等生理過(guò)程。tau基因定位于17號(hào)染色體，含堿基100 kb，16個(gè)外顯子，其結(jié)構(gòu)被分為N端、脯氨酸富含區(qū)域、微管結(jié)合區(qū)域和C端4部分。其中的脯氨酸富含區(qū)含有許多磷酸化位點(diǎn)，能被其它蛋白包括酪氨酸激酶Fyn的SH3結(jié)構(gòu)域識(shí)別，進(jìn)而發(fā)生磷酸化修飾，參與tau生理和病理功能的調(diào)控[1]。目前的研究發(fā)現(xiàn)，與成熟腦相比發(fā)育腦的tau呈現(xiàn)特殊的磷酸化，并在髓鞘化進(jìn)程中發(fā)揮重要作用。

2 發(fā)育腦tau的特點(diǎn)

2.1 Tau參與調(diào)控軸突生長(zhǎng)和神經(jīng)元遷移 Takei等[2]的研究發(fā)現(xiàn)，敲除tau和MAP1B基因后，小鼠出現(xiàn)神經(jīng)元軸突生長(zhǎng)抑制和遷移障礙。該項(xiàng)研究采用tau缺陷小鼠(tau-)和MAP1B缺陷小鼠(MAP1B-)繁育出具有C57BL/6J (>93%) ×129/Sv (< 7%)遺傳背景的tau-/-MAP1B-/-、tau+/+MAP1B-/-、tau-/-MAP1B+/+轉(zhuǎn)基因小鼠，在出生后0.5 d(postnatal 0.5 days，P0.5d)和出生后4周(postnatal 4 weeks，P4w)對(duì)tau+/+MAP1B+/+、tau+/+MAP1B-/-、tau-/-MAP1B+/+和tau-/-MAP1B-/-小鼠的腦組織進(jìn)行研究。電鏡觀察結(jié)果顯示，3種基因缺陷的小鼠均發(fā)生了神經(jīng)元軸突生長(zhǎng)抑制、神經(jīng)元層和生長(zhǎng)錐中MT數(shù)量減少；細(xì)胞培養(yǎng)和體外遷移分析揭示，3種基因缺陷小鼠的小腦神經(jīng)元遷移延遲、神經(jīng)突延長(zhǎng)障礙；免疫組織化學(xué)結(jié)果提示，3種基因缺陷小鼠的海馬均出現(xiàn)錐體細(xì)胞排列松散，胞體間失去聯(lián)系；此外，tau-/-、MAP1B-/-缺陷可引起前聯(lián)合、胼胝體體積明顯減小，出現(xiàn)嚴(yán)重的軸突束發(fā)育不良，這種改變?cè)趖au-/-MAP1B-/-、tau-/-MAP1B+/+小鼠腦組織中更加明顯?？梢?，在中樞神經(jīng)發(fā)育過(guò)程中，tau對(duì)調(diào)控軸突生長(zhǎng)和神經(jīng)元遷移發(fā)揮了重要的作用。

2.2 發(fā)育腦tau磷酸化的規(guī)律及其可能的調(diào)控 Tau磷酸化與去磷酸化作用的平衡是維持其功能穩(wěn)定的重要調(diào)控機(jī)制。異常高度磷酸化的tau可與正常tau、MAP1、MAP2結(jié)合，競(jìng)爭(zhēng)性抑制后3者與MT的結(jié)合；磷酸化作用使tau聚合形成雙螺旋細(xì)絲，后者進(jìn)一步磷酸化聚合形成神經(jīng)纖維纏結(jié)(neurofibrillary tangles，NFTs)，參與中樞神經(jīng)系統(tǒng)功能紊亂?？梢?，tau的正常磷酸化水平在維系中樞的正常功能中發(fā)揮著重要作用。

Yu 等[3]對(duì)胚胎期15 d(embryonic 15 days，E15d)至出生后24月(postnatal 24 months，P24m)Wistar大鼠腦內(nèi)總tau、14個(gè)位點(diǎn)的磷酸化水平以及蛋白激酶和磷酸脂酶(phosphatase，PP)的活性變化進(jìn)行研究后發(fā)現(xiàn)，在胚胎早期胎鼠腦與人類胎腦組織一樣，僅表達(dá)最短亞型的tau(0N3R tau352)，P5d后開始出現(xiàn)較長(zhǎng)亞型，P15d至P1m腦內(nèi)出現(xiàn)全部tau亞型(0N3R tau352、1N3R tau381、2N3R tau410、0N4R tau383、1N4R tau412、2N4R tau441)，而P3 m后胎兒期的tau亞型消失，只表達(dá)4R tau。根據(jù)發(fā)育腦tau磷酸化水平的變化規(guī)律可將其14個(gè)磷酸化位點(diǎn)分為3組。第1組：胚胎期開始出現(xiàn)高磷酸化水平，并持續(xù)至P15d。包括Ser202、Thr212、Thr217、Ser356、Ser404、Ser409。第2組：磷酸化水平自胚胎期逐漸升高至P5d或P15d達(dá)到高峰，從P1～3m開始逐漸降低至成年水平。包括Thr181、Ser199、Thr205、Ser214、Ser262、Ser422。第3組：在胚胎期和成年期磷酸化水平一直保持穩(wěn)定，包括Thr231和Ser396兩個(gè)位點(diǎn)。其中，第1、2組位點(diǎn)磷酸化水平的變化規(guī)律與胚胎、新生鼠早期神經(jīng)突的生長(zhǎng)期一致，提示這些位點(diǎn)的磷酸化可能與神經(jīng)突的發(fā)育有關(guān)。

此外，Yu等[3]還對(duì)幾種主要的蛋白激酶和PP對(duì)胚胎及新生鼠時(shí)期腦tau磷酸化水平的影響進(jìn)行了研究，結(jié)果顯示，糖原合成激酶 3β(glycogen synthase kinase 3β，GSK-3β)的表達(dá)在胚胎期與第2組位點(diǎn)的高磷酸化水平一致；細(xì)胞周期蛋白依賴性激酶5在胚胎發(fā)育期持續(xù)增高，并在P15d到達(dá)頂點(diǎn)，此高表達(dá)持續(xù)至P24m；細(xì)胞外調(diào)節(jié)蛋白激酶、JNKs在胚胎發(fā)育期表達(dá)增多，并分別在P5～15d、P0～15d達(dá)到頂峰，其后逐漸下降趨于穩(wěn)定；蛋白激酶A在胚胎發(fā)育期及P5d也呈現(xiàn)升高。蛋白激酶對(duì)tau磷酸化作用進(jìn)行調(diào)節(jié)，而PP1、PP2A、PP2B和PP5對(duì)tau的去磷酸化作用進(jìn)行調(diào)控。該研究發(fā)現(xiàn)，除PP1表達(dá)水平在整個(gè)發(fā)育和成熟期都趨于穩(wěn)定外，PP2A、PP2B和PP5表達(dá)水平在發(fā)育期呈逐漸升高的趨勢(shì)，在P15d達(dá)到頂峰并穩(wěn)定于該水平。

可見，發(fā)育腦tau存在特殊的磷酸化及調(diào)控表現(xiàn)，其可能的調(diào)控紊亂，在發(fā)育期的多種中樞神經(jīng)系統(tǒng)疾病尤其是新生兒缺氧缺血性腦病(hypoxia-ischemia encephalopathy，HIE)的病理生理過(guò)程中發(fā)揮的作用，有待進(jìn)一步研究。

2.3 發(fā)育期腦tau磷酸化和成熟腦tau病理性磷酸化的比較 與發(fā)育期腦相比，阿爾茨海默病(Alzheimer's disease，AD)患者腦tau在Ser 202、Thr212、Thr217、Thr231、Ser396、Ser404、Ser422位點(diǎn)磷酸化水平升高；Thr181、Ser199、Thr205、Ser214、Ser262、Ser356、Ser409磷酸化水平接近或低于發(fā)育期[3]。正常胚胎期及出生后早期腦內(nèi)高度磷酸化的位點(diǎn)，與AD中異常高度磷酸化并參與NFTs形成的位點(diǎn)重疊?？梢?，tau某些位點(diǎn)的高度磷酸化也許是正常腦發(fā)育所必需，但在成年期卻參與了中樞退化性疾病的發(fā)生，機(jī)制不明。

Duka等[4]對(duì)AD和帕金森癥(Parkinson’s disease，PD)、路易氏小體癡呆(dementia with Lewy bodies，DLB)患者腦tau磷酸化水平進(jìn)行研究后發(fā)現(xiàn)，與同齡對(duì)照組相比，3種疾病中tau多個(gè)位點(diǎn)的磷酸化水平出現(xiàn)增高，見表1。發(fā)育腦與神經(jīng)退行性疾病患者腦tau特定位點(diǎn)磷酸化水平的相關(guān)性，為進(jìn)一步研究不同發(fā)育階段病理情況下腦tau異常修飾提供了新的思路。

此外，Zhong等[5]的研究發(fā)現(xiàn)，表達(dá)外顯子2、10的tau亞型在磷酸化水平增高的情況下形成tau低聚物的能力增強(qiáng)。異常高度磷酸化的tau與4R tau結(jié)合的能力高于3R tau，這種結(jié)合能力由強(qiáng)及弱依次為：2N4R>1N4R>0N4R，1N4R>1N3R>0N3R[6]。0N3R tau是與異常高度磷酸化的tau結(jié)合能力最低的亞型，這可能與發(fā)育腦tau(主要以0N3R tau為主)在高磷酸化水平的情況下沒有出現(xiàn)異常聚集有關(guān)。

3 Tau與新生兒缺氧缺血性腦損傷

HIE是缺氧和腦血流減少所致的胎兒和/或新生兒的腦損傷。目前尚無(wú)直接證據(jù)表明tau參與HIE的發(fā)病，但2013年日本學(xué)者發(fā)現(xiàn)，室息患兒血清tau水平升高并與患兒臨床表現(xiàn)的嚴(yán)重程度呈現(xiàn)顯著正相關(guān)[7]。這提示，tau的病理性改變可能參與了HIE的發(fā)病過(guò)程。在中樞退行性變中，tau的病理作用重點(diǎn)體現(xiàn)于NFTs的形成，后者參與了神經(jīng)元軸突運(yùn)輸障礙等病理過(guò)程。胎腦內(nèi)tau雖然呈現(xiàn)高磷酸化趨勢(shì)，但目前尚無(wú)研究證實(shí)HIE患兒腦內(nèi)出現(xiàn)神經(jīng)纖維纏結(jié)或tau的其它病理性改變。tau的病理作用是否可以獨(dú)立于神經(jīng)纖維纏結(jié)而存在？

表1 正常成人、同齡組神經(jīng)退行性疾病及發(fā)育腦內(nèi)tau高磷酸化位點(diǎn)的比較

Hyperphosphorylation sites were shown in the table in AD postmortem frontal cortex (n=5～6) compared with non-diseased controls (n=4～6). Ser202, Thr205, Thr212, Ser235, Ser238, Ser262, Ser356, Ser396, Ser404, Ser409, Ser413, Ser422 sites phosphorylation elevated compared with non-diseased controls (n=7) in PD postmortem frontal cortex or corpus striatum (n=7～9). tau phosphorylation increased in Thr212, Ser214, Thr217, Thr231,Ser238,Ser396,Ser404,Ser422 sites compared with non-diseased controls (n=7～10) in DLB postmortem frontal cortex (n=7～10). tau Thr181,Ser202,Thr205,Thr212,Ser214,Thr217,Ser262,Ser356,Ser404,Ser409,Ser422 sites are hyperphosphorylation in development brain and they are overlapping with adult PD/AD/DLB hyperphosphorylation sites (n=4～6).

與病理性磷酸化的tau不同，NFTs不能競(jìng)爭(zhēng)性結(jié)合MT并使MT穩(wěn)定性降低[8]。過(guò)表達(dá)p25的轉(zhuǎn)基因小鼠tau磷酸化作用增強(qiáng)，在未發(fā)現(xiàn)神經(jīng)纖維纏結(jié)的情況下，出現(xiàn)細(xì)胞骨架紊亂、軸索腫脹，軸漿內(nèi)的線粒體、溶酶體聚集成團(tuán)，這些改變與MT功能的喪失一致[9-10]。tau異常引起突觸損傷、脫失，在NFTs形成和神經(jīng)元凋亡之前就已經(jīng)出現(xiàn)[11]。tau基因缺失可導(dǎo)致AD動(dòng)物模型的白質(zhì)束和神經(jīng)纖維網(wǎng)的軸突球狀體形成[12]，而營(yíng)養(yǎng)障礙性神經(jīng)網(wǎng)軸突球狀體為AD的顯著特征之一?？梢?，tau介導(dǎo)的神經(jīng)毒性并不依賴神經(jīng)纖維纏結(jié)的形成，其病理性磷酸化足以導(dǎo)致神經(jīng)細(xì)胞損傷。

3.1 缺氧缺血與tau病理性修飾 HIE的發(fā)病環(huán)節(jié)之一是缺血所致腦內(nèi)糖代謝低下。對(duì)AD患者的研究中發(fā)現(xiàn)[13]，O-GlcNAc糖基化參與調(diào)節(jié)腦內(nèi)tau磷酸化水平。饑餓小鼠因腦內(nèi)糖代謝低下，導(dǎo)致細(xì)胞內(nèi)尿苷二磷酸-N-乙酰葡萄糖胺濃度下降，O-GlcNAc糖基化作用降低，進(jìn)而引起tau磷酸化水平增高。Liu等[14]尸檢提取AD患者和對(duì)照組額葉皮質(zhì)，對(duì)tau不同位點(diǎn)的磷酸化水平和O-GlcNAc糖基化水平行相關(guān)性分析，結(jié)果顯示：tau磷酸化水平與O-GlcNAc糖基化作用呈負(fù)相關(guān)。O-GlcNAc糖基化作用下降后AD患者腦tau在Ser199、Ser202、Thr205、Thr212、Ser214、Thr217、Ser262、Ser396、Ser422位點(diǎn)磷酸化水平顯著升高；此外，該研究還發(fā)現(xiàn)，AD組葡萄糖轉(zhuǎn)運(yùn)體(glucose transporter，GLUT)1和GLUT3表達(dá)水平下降，與tau的O-GlcNAc糖基化水平降低存在相關(guān)性。

HIE后機(jī)體還存在應(yīng)激反應(yīng)。Rissman等[15]研究發(fā)現(xiàn)，急性應(yīng)激后可導(dǎo)致糖皮質(zhì)激素水平增高、海馬GSK-3β活化，同時(shí)tau在Thr181、Ser199 、Thr212、Thr231等多個(gè)位點(diǎn)出現(xiàn)磷酸化水平升高。該研究還發(fā)現(xiàn)，抑制糖皮質(zhì)激素作用并不能影響tau的磷酸化水平，而敲除轉(zhuǎn)基因小鼠的Ⅰ型腎上腺素釋放因子受體，能夠抑制GSK-3β活化，降低tau磷酸化水平；敲除2型腎上腺素釋放因子受體可使GSK-3β活化明顯增多，tau磷酸化作用增強(qiáng)?？梢?，急性應(yīng)激后GSK-3β活化調(diào)控可能與腎上腺素釋放因子受體有關(guān)。該受體調(diào)控的信號(hào)轉(zhuǎn)導(dǎo)機(jī)制尚有待進(jìn)一步研究。

3.2 Tau與髓鞘化之間的關(guān)系 髓鞘形成是大腦發(fā)育的必經(jīng)之路，作為絕緣層的髓鞘脂包繞于神經(jīng)元軸突，保證了軸突的正?？焖匐妭鲗?dǎo)。少突膠質(zhì)細(xì)胞(oligodendroglia, OL)是形成中樞神經(jīng)系統(tǒng)髓鞘的細(xì)胞，少突膠質(zhì)細(xì)胞前體細(xì)胞(oligodendrocyte progenitor cells，OLPs)的受損，并由此導(dǎo)致腦髓鞘化低下是HIE遠(yuǎn)期行為異常的機(jī)制之一。目前的研究認(rèn)為，tau在OL尤其是OLPs上表達(dá)，并參與調(diào)控髓鞘化進(jìn)程。

3.2.1 “Fyn-tau-MT”綁定與OL分化 在髓鞘化過(guò)程中，軸突源信號(hào)被OL的膜受體識(shí)別并激活Fyn，后者調(diào)控OL增殖分化及髓鞘堿性蛋白(myelin basic protein, MBP)合成。Fyn調(diào)控軸突-OL信號(hào)轉(zhuǎn)導(dǎo)的機(jī)制，見圖1[16]。在此，“Fyn-tau-MT”綁定在OL分化中發(fā)揮了重要作用。Klein等[17]發(fā)現(xiàn)，具有活性的Fyn與喪失了MT結(jié)合能力的突變tau結(jié)合，致使OL分化的數(shù)量和長(zhǎng)度出現(xiàn)明顯下降。Reynolds等[1]的研究發(fā)現(xiàn)，tau的磷酸化降低了其與Fyn的綁定能力；Leugers等[18]的研究也表明，Ser199/202的異常磷酸化作用削弱了0N3R tau與Fyn SH3結(jié)構(gòu)域的綁定能力?？梢姡毖跞毖髏au病理性修飾，可能使“Fyn -tau-MT”綁定能力下降，阻斷Fyn下游信號(hào)轉(zhuǎn)導(dǎo)途徑，導(dǎo)致髓鞘化受損。

Figure 1.The role of Fyn as central integrator and mediator of axon-glia signalling[16]. Axon-derived signals are sensed by oligodendroglial membrane receptors modulate Fyn kinase activity. Upon dephosphorylation of the C-terminus with the conserved regulatory tyrosine residue 531 (Y531), the conformation changes to an open form that is regarded as the active state. Fyn mediates downstream signalling that can be divided into three major pathways: (1) the RhoA/Cdc42/Rac1-dependent pathway modulates actin dynamics and mediates cell survival and morphological differentiation; (2) recruitment of the microtubule cytoskeleton contributes to cell polarisation and may facilitate axon-directed cargo transport; (3) activated Fyn controls localised myelin protein synthesis by affecting mRNA transport, stability, and translational regulation. In summary, these pathways integrate axonal signals to spatiotemporally regulate myelin formation.

Figure 2.The mechanism of tau protein abnormal modified after cerebral hypoxia-ischemia.There are 5 possible pathways in hypoxia-ischemi-related tau protein hyperphosphorylation. (1) Acute stress response. It was arisen from hypoxic-ischemic stimulation and it could activate GSK-3β through corticotropin-releasing factor receptors. It can lead to tau hyperphosphorilized in hippocampus. (2) Glucose low metabolism. GLUTs level decreased after energy depletion in hypoxic-ischemic injury. And then it can reduce O-GlcNAc glycosylation which cause tau protein hyperphsphorylation. (3) Microglial cell activation. Microglial cells could be activated by ATP, an important neurotransmmiter which can release from dead cell after hypoxic-ischemic damage. ATP works as a microglial cell activator which can induce cytokine overexpression. (4) Glutamate metabolism. Glutamate released from dead neurons and oligodendrocyte progenitor cells. It causes intracellular Ca2+ overload that promotes GSK-3β activity and leads to tau hyperphosphorylation by glutamate receptors. In addition, glutamate can cause Zn2+ release, it inhibits PP2A activity that should result in tau protein dephosphorylation then causes tau protein hyperphosphorylation; (5) Fyn overexpression. Fyn expression elevated after hypoxic-ischemic damage and it takes part in tyrosine site phosphorylation in tau protein. Though the direct relationship between hypoxic-ischemic encephalopathy is absent, these potential mechanisms mentioned above should be involved in hypoxia-ischemia-related tau protein abnormal modification. Consequently, neuron lost, oligodendrocyte differentiation inhibition, MBP synthesis decreasing, mitochondria and axon dysfunction will occur after tau abnormal modification.

3.2.2 Tau與MBP合成 MBP是成熟中樞神經(jīng)系統(tǒng)髓鞘的主要蛋白質(zhì)。MBP的mRNA包含于RNA轉(zhuǎn)運(yùn)顆粒內(nèi)，通過(guò)RNA異質(zhì)核糖核蛋白A2的3′UTR序列與tau結(jié)合，以MT為運(yùn)輸軌道被轉(zhuǎn)運(yùn)至OL的質(zhì)膜，在Fyn的調(diào)控下合成MBP。tau的病理性磷酸化會(huì)導(dǎo)致MT穩(wěn)定性下降，影響MBP的RNA轉(zhuǎn)運(yùn)顆粒運(yùn)輸。

在此，F(xiàn)yn活化是髓鞘化的中心環(huán)節(jié)，但Fyn的過(guò)度活化也具有毒性作用。在過(guò)度表達(dá)Fyn的小鼠上復(fù)制HIE模型后，發(fā)現(xiàn)小鼠腦損傷加重、死亡率增加[19]。Fyn的高表達(dá)可導(dǎo)致tau在Ty18位點(diǎn)出現(xiàn)磷酸化水平增高，拮抗Fyn的活性能減輕AD患者腦內(nèi)tau的病理性磷酸化作用[20]?？梢姡現(xiàn)yn的適度活化是正常中樞髓鞘化的關(guān)鍵。

3.3 HIE后腦內(nèi)炎癥反應(yīng)與tau病理性修飾 感染/炎癥反應(yīng)在HIE中發(fā)揮重要作用。HIE后腦內(nèi)的炎癥反應(yīng)主要由腦內(nèi)阿米巴樣小膠質(zhì)細(xì)胞(amoeboid microglial cell，AMC)介導(dǎo)發(fā)生[21]。缺氧后腦組織中游離的三磷酸腺苷增多[22]，可能通過(guò)調(diào)節(jié)P2X4受體誘導(dǎo)AMC活化[23]，后者進(jìn)一步釋放炎癥因子，包括白介素1β(interleukin 1β，IL-1β)、腫瘤壞死因子α(tumor necrosis factor，TNF-α)等。Munoz等[24]研究顯示TNF-α、IL-1β等可活化神經(jīng)元上絲裂原活化蛋白激酶(mitogen- activated protein kinase，MAPK)信號(hào)途徑，使tau磷酸化作用增強(qiáng)。Ghosh等[25]對(duì)轉(zhuǎn)基因小鼠(3×TgAD/IL-1βXAT基因表達(dá)1、3 月后)進(jìn)行研究后發(fā)現(xiàn)，IL-1β釋放和小膠質(zhì)細(xì)胞(microglial cells，MCs)活化可相互促進(jìn)，并促使海馬區(qū)域p38 MAPK、GSK-3β活化，導(dǎo)致tau異常過(guò)度磷酸化。

3.4 谷氨酸代謝障礙與tau磷酸化的雙向作用 缺氧性腦損傷發(fā)生后，腦內(nèi)谷氨酸釋放增多。Sun等[26]將培養(yǎng)的海馬腦片和原代神經(jīng)元暴露在谷氨酸中，tau在Thr205、Thr231、Ser396和Ser404位點(diǎn)出現(xiàn)高度磷酸化。異常過(guò)度磷酸化的tau可引起線粒體功能障礙，興奮性氨基酸轉(zhuǎn)運(yùn)體(excitatory amino acid transporters，EAATs)功能受損，使谷氨酸在突觸部位的清除能力降低并逆向轉(zhuǎn)運(yùn)，導(dǎo)致細(xì)胞外谷氨酸大量聚集，谷氨酸受體持續(xù)活化。谷氨酸受體的過(guò)度活化介導(dǎo)Ca2 +內(nèi)流，細(xì)胞內(nèi)Ca2 +超載，進(jìn)而激活GSK-3β，鈣離子/ 鈣調(diào)節(jié)蛋白依賴性蛋白激酶Ⅱ(Ca/calmodulin- dependent protein kinases or CaM kinases Ⅱ，CaMK Ⅱ)，MAPK等途徑引起 tau的過(guò)度磷酸化。此外[26-27]，突觸的谷氨酸釋放伴隨鋅(Zinc, Zn2 +)釋放，Zn2 +能夠抑制PP2A活性，從而進(jìn)一步促進(jìn)tau異常高度磷酸化(HIE后，tau病理性修飾及其介導(dǎo)腦損傷的機(jī)制見圖2)。

3.5 HIE后血清tau的改變與腦損傷的關(guān)系 Lilianga等[28]對(duì)創(chuàng)傷后大鼠血清tau表達(dá)的研究表明，血清tau水平與腦損傷的程度呈正相關(guān)。Tunc等[29]研究分娩方式對(duì)臍帶血內(nèi)tau水平的影響時(shí)發(fā)現(xiàn)，胎兒缺氧時(shí)腦tau可釋放至血清，tau可作為反映胎兒缺氧情況的指標(biāo)。Takahashi等[7]將P0 d、P3 d、P7 d窒息患兒血清與同齡正常新生兒血清中tau水平進(jìn)行比較后發(fā)現(xiàn)，P3 d、P7 d時(shí)窒息患兒血清tau水平明顯高于正常對(duì)照組，且血清tau水平與臨床表現(xiàn)的嚴(yán)重程度呈正相關(guān)。

4 展望

隨著新生兒醫(yī)學(xué)的發(fā)展，早產(chǎn)兒的存活率明顯提高，但是幸存早產(chǎn)兒常合并腦損傷，可引起痙攣性腦癱、認(rèn)知及視聽障礙等遠(yuǎn)期行為異常。學(xué)習(xí)記憶的生理和病理過(guò)程與海馬多種蛋白的表達(dá)，以及正常的髓鞘化具有密切關(guān)系，其中tau是學(xué)習(xí)記憶的重要標(biāo)記性蛋白。目前的研究發(fā)現(xiàn)，急性腦缺氧缺血后MC活化、炎癥因子、谷氨酸釋放增多，以及葡萄糖攝取/代謝障礙、急性應(yīng)激等病理情況均可誘導(dǎo)腦tau的病理性修飾，后者在神經(jīng)元凋亡、OL分化障礙和突觸功能退化、突觸丟失等病理改變中發(fā)揮重要作用。

然而，tau可以發(fā)生磷酸化的位點(diǎn)很多，哪些位點(diǎn)的病理性磷酸化與HIE的發(fā)病相關(guān)，仍然不清。雖有研究表明[7]，血清tau水平與窒息患兒臨床表現(xiàn)的嚴(yán)重程度呈正相關(guān)，但血清tau要作為新生兒HIBD嚴(yán)重程度的評(píng)價(jià)指標(biāo)，要求其具有特異性及穩(wěn)定性。而臨床中新生兒、尤其是早產(chǎn)兒HIE的發(fā)生多伴隨有病理性黃疸、呼吸窘迫綜合征和新生兒肺炎等合并癥，這是否會(huì)影響血清tau水平？血清tau在HIE腦損傷中的特異性監(jiān)測(cè)作用，尚需要大樣本的研究進(jìn)行驗(yàn)證，以及對(duì)對(duì)照組進(jìn)行嚴(yán)格地篩選方能得到可信的數(shù)據(jù)。

綜上所述，腦tau的病理性修飾與HIE的發(fā)生、發(fā)展密切相關(guān)。雖然相關(guān)研究面臨許多困難和挑戰(zhàn)，但是研究tau在HIE中的可能作用及其機(jī)制，探討缺氧缺血后血清tau與腦tau間的可能關(guān)系，有望為HIE的防治提供新的思路。

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Abnormally modified tau and hypoxic-ischemic brain damage

XIAO Jie, LI Fan

(DepartmentofPathologyandPathophysiology,BasicMedicalCollege,KunmingMedicalUniversity,Kunming650500,China.E-mail:leefan623@sina.com)

Tau is the most abundant microtubule-associated protein in the brain. If tau protein lost the normal function, the toxic effect should be showed and plays an important role in various central nervous system lesions. Hypoxic-ischemic encephalopathy (HIE) is an important cause of mortality in the neonatal period and it is mainly characterized by neurological deficits such as cognitive limitations. However， the mechanism still needs further study, and the underlying relationship between tau protein and HIE lacks direct evidence. Some recent clinical study reported that tau protein expression elevated in the serum of asphyxia children and had a high correlation with behavior deficient. In this review, we focus on 3 key points to provide new insights to understand the tau protein-related pathogenesis of HIE as followed: (1) tau protein and its phosphorylation change during central nervous system development; (2) comparison of tau protein expression in developing brain and adult brain under some neurological disorders; (3) potential pathological change of tau in HIE related pathological conditions, such as dysmyelination, inflammation response and glutamate metabolism.

蛋白質(zhì)， tau； 缺氧缺血性腦損傷； 髓鞘形成障礙； 谷氨酸代謝

Protein, tau; Hypoxic-ischemic brain damage; Dysmyelination; Glutamate metabolism

1000- 4718(2015)01- 0181- 07

2014- 06- 09

2014- 10- 23

國(guó)家自然科學(xué)基金資助項(xiàng)目(No. 81200939； No. 31260242)； 云南自然科學(xué)基金資助項(xiàng)目(No. 2011FB060)

△通訊作者 Tel: 0871-659228958; E-mail: leefan623@sina.com

R363

A

10.3969/j.issn.1000- 4718.2015.01.034