茶多酚對(duì)阿爾茨海默病的防治功能與機(jī)理研究進(jìn)展

魏然，徐平，應(yīng)樂，王岳飛

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茶多酚對(duì)阿爾茨海默病的防治功能與機(jī)理研究進(jìn)展

魏然，徐平*，應(yīng)樂，王岳飛

浙江大學(xué)茶學(xué)系，浙江 杭州 310058

阿爾茨海默病作為一種神經(jīng)退行性疾病，因與認(rèn)知功能相關(guān)的神經(jīng)元異常而導(dǎo)致記憶衰退，甚至影響自主行動(dòng)和吞咽。茶多酚能夠有效防治阿爾茨海默病，其機(jī)制主要包括阻礙異常蛋白積累、抗氧化、影響神經(jīng)遞質(zhì)水平、調(diào)節(jié)細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)通路及抗炎等。本文就近年來茶多酚對(duì)阿爾茨海默病的防治功能與機(jī)理方面的研究進(jìn)行綜述。

阿爾茨海默?。徊瓒喾?；異常蛋白；神經(jīng)遞質(zhì)；抗炎

2015年世界衛(wèi)生組織的調(diào)查顯示，神經(jīng)退行性疾病已成為發(fā)達(dá)國家中引起死亡的三大因素之一[1]。阿爾茨海默?。ˋlzheimer's disease，AD）作為神經(jīng)退行性疾病中發(fā)病率最高的病種，約占老年癡呆癥的80%[2]。以美國為例，目前每67?s會(huì)產(chǎn)生1例AD，預(yù)計(jì)到2050年，每33?s將產(chǎn)生1例，全世界每85人將有1人患病[3]。盡管每年關(guān)于AD的研究論文超過10?000篇，但目前仍未找到有效的預(yù)防措施和明確的診治方法[4]。AD患者由于其神經(jīng)元和突觸的正常功能異常，導(dǎo)致腦功能的進(jìn)行性退化[3]。AD患者腦內(nèi)易受侵害的區(qū)域包括：基底前腦、杏仁體、海馬體、內(nèi)嗅皮層、新皮質(zhì)及某些腦干核[5]。目前一線治療藥物主要包括乙酰膽堿酯酶抑制劑及N-甲基-D-天冬氨酸（N-Methyl-D-aspartic, NMDA）拮抗劑，藥效低，且大多具有副作用。AD的發(fā)生受多種因素影響，主要包括：異常蛋白積累、氧化應(yīng)激、膽堿能缺失、興奮性神經(jīng)毒性、炎癥、細(xì)胞信號(hào)通路異常等。

茶多酚作為茶葉中最主要的活性物質(zhì)，具有防癌、抗炎、保護(hù)心腦血管等功效，近年來茶多酚在神經(jīng)保護(hù)方面的作用不斷引起人們的關(guān)注，并在體外和動(dòng)物模型中得以證實(shí)。如經(jīng)茶多酚處理之后，可顯著改善認(rèn)知功能，抑制淀粉樣蛋白積累和tau蛋白的磷酸化；防止氧化應(yīng)激；調(diào)節(jié)細(xì)胞信號(hào)通路及細(xì)胞凋亡因子的表達(dá)；調(diào)節(jié)神經(jīng)遞質(zhì)水平及抑制炎癥發(fā)生等。本文就茶多酚防治阿爾茨海默病的研究現(xiàn)狀及機(jī)理進(jìn)行系統(tǒng)綜述。

1 茶多酚對(duì)AD的防治作用

1.1 流行病學(xué)

伴隨年齡的增長，腦萎縮和認(rèn)知功能損傷難以避免，延遲腦老化對(duì)于提高老年人生活品質(zhì)至關(guān)重要。茶對(duì)人體認(rèn)知能力改善的實(shí)證研究較少，先前關(guān)于飲茶能夠改善認(rèn)知功能的記錄見表1[6]，其中4個(gè)調(diào)查研究分別來自于日本[7]、新加坡[8-9]和挪威[10]，結(jié)果均顯示茶葉消費(fèi)量與老年認(rèn)知功能改善具有相關(guān)性，但在作用效果方面茶類間存在差異。2014年日本一項(xiàng)調(diào)查也顯示，綠茶能夠有效恢復(fù)認(rèn)知功

能，而紅茶效果不佳，與不飲用綠茶者相比，每周1天以上飲用綠茶的消費(fèi)者患癡呆和認(rèn)知損傷的概率顯著下降[11]。

1.2 體外研究

探究茶多酚對(duì)于神經(jīng)細(xì)胞的保護(hù)作用通常選取腎上腺嗜鉻細(xì)胞瘤細(xì)胞PC12，它可表現(xiàn)出神經(jīng)元特性，廣泛應(yīng)用于神經(jīng)系統(tǒng)疾病的體外研究。Liu J C等[12]發(fā)現(xiàn)，兒茶素可以顯著提高暴露于100?μmol·L-1Pb2+的PC12細(xì)胞的細(xì)胞活性，降低胞內(nèi)Ca2+水平，減少ROS的生成，其中帶有沒食子?；膬翰杷剌^不帶沒食子?；膬翰杷匦Ч?。Ji Y J等[13]發(fā)現(xiàn)，EGCG可以抑制NO誘導(dǎo)的大鼠PC12細(xì)胞形態(tài)的改變，減少ROS的生成和細(xì)胞色素C的釋放，抑制caspase-9、caspase-8和caspase-3的激活。Haider R和Annie J[14]也發(fā)現(xiàn)，兒茶素可抑制多聚不飽和脂肪酸氧化產(chǎn)物4-羥基壬烯醛（4-Hydroxynonenal, 4-HNE）誘導(dǎo)的PC12細(xì)胞中ROS的生成，影響谷胱甘肽代謝，減少脂質(zhì)過氧化和蛋白質(zhì)氧化，但同時(shí)也發(fā)現(xiàn)較高濃度的EGCG（100?μmol·L-1）和紅茶茶多酚（5?μg·mL-1、10?μg·mL-1）會(huì)損害DNA，釋放細(xì)胞色素C，激活caspase-3。

1.3 動(dòng)物實(shí)驗(yàn)

通常選取快速老化小鼠SAMP8和SAMP10進(jìn)行試驗(yàn)，SAMP小鼠對(duì)于研究AD相關(guān)的神經(jīng)退行性疾病是一種相當(dāng)理想的動(dòng)物模型。Yin C C等[15]人使用6個(gè)月大的SAMP8小鼠進(jìn)行試驗(yàn)，發(fā)現(xiàn)連續(xù)飲用烏龍茶、綠茶16周均能抑制認(rèn)知損傷，減少腦組織海綿狀變性及脂褐質(zhì)沉積。Tranum K等[16]發(fā)現(xiàn)，飲用0.5%綠茶提取物水溶液8周也可顯著提高12個(gè)月大的老年雄性Wistar大鼠的學(xué)習(xí)和記憶能力，同時(shí)顯著降低乙酰膽堿酯酶活性。Li Q等[17]發(fā)現(xiàn)4個(gè)月大的雄性SAMP8小鼠連續(xù)飲用6個(gè)月0.05%和0.1%的綠茶兒茶素溶液，可預(yù)防空間學(xué)習(xí)能力和記憶力的衰退，海馬部異常蛋白表達(dá)下降，腦萎縮和DNA氧化損傷均有所改善。

2 作用機(jī)理

2.1 抑制異常蛋白積累

多酚類物質(zhì)能夠與多肽或蛋白質(zhì)發(fā)生反應(yīng)，具有抗異常蛋白積累的作用。β-淀粉樣蛋白（Amyloid β-protein, Aβ）的積累和tau蛋白的過度磷酸化是AD發(fā)病的重要特征?！暗矸蹣拥鞍准僬f”于1991年提出，該假說認(rèn)為細(xì)胞外Aβ多肽的沉積是AD發(fā)病的首要原因[18]。Aβ多肽是淀粉樣前體蛋白（Amyloid precursor protein, APP）分裂的產(chǎn)物，Aβ多肽聚集形成低聚體后又進(jìn)一步沉積形成淀粉樣蛋白斑塊的老年斑，已被證實(shí)與神經(jīng)元死亡有密切關(guān)系。APP有兩種加工方式：正常情況下，通過α分泌酶將APP水解成可溶性APP（sAPPα），具有神經(jīng)保護(hù)作用；異常情況下，APP在β分泌酶的作用下，釋放可溶性的sAPPβ，剩下包含99個(gè)氨基酸的淀粉樣肽再在γ分泌酶的作用下，形成含有40或42個(gè)氨基酸的難溶性的淀粉樣肽，即為Aβ40和Aβ42[4,19-20]。Aβ多肽的毒性取決于其構(gòu)象及長度，Aβ42比Aβ40毒性要大，Aβ42聚集形成的低聚體毒性更大[21]。茶多酚可以通過調(diào)節(jié)α、β、γ分泌酶的活性從而抑制Aβ低聚體的形成，且EGCG單體清除Aβ的能力要強(qiáng)于茶多酚復(fù)合物[22]。在APP基因過度表達(dá)的小鼠中，Kavon R Z等[23]發(fā)現(xiàn)，通過靜脈注射20?mg·kg-1EGCG可以提高α分泌酶的活性，抑制Aβ多肽的形成。在早老素2（Presenilin 2, PSEN2）基因突變的AD小鼠模型中，口服EGCG水溶液可以改善記憶功能，提高α分泌酶活性，降低β分泌酶和γ分泌酶活性，從而降低Aβ水平[24]。在脂多糖誘導(dǎo)的AD小鼠模型中，發(fā)現(xiàn)通過口服EGCG（1.5、3?mg·kg-1）3周可以減弱β分泌酶和γ分泌酶的活性，炎癥蛋白、誘導(dǎo)型一氧化氮合成酶（Induced nitric oxide synthase, iNOS）和環(huán)氧合酶（Cyclo oxygenase, COX）表達(dá)量減少[25]。在已分化的PC12細(xì)胞模型中，通過體外模擬胃腸消化液并獲得其中的綠茶提取物（不再具有黃烷醇結(jié)構(gòu)），發(fā)現(xiàn)其質(zhì)量濃度在0.030~0.125?μg·mL-1時(shí)可以抑制Aβ42的生成[26]。多酚類物質(zhì)作用于Aβ的機(jī)理大致可以歸于以下兩點(diǎn)：首先，茶多酚可以和Aβ多肽結(jié)合，使之形成無毒的球形寡聚物[27]。核磁共振探測到EGCG直接與Aβ多肽單體結(jié)合，使具有穩(wěn)定Aβ多肽作用的芳香疏水核心受到干擾。Aβ的C末端（殘基22~39）形成β折疊構(gòu)型，而N末端（殘基1~20）則非結(jié)構(gòu)化。EGCG誘導(dǎo)天然未折疊的多肽形成穩(wěn)定的低聚體結(jié)構(gòu)，可能會(huì)阻止原纖維形成，同時(shí)阻止纖維生成過程中產(chǎn)生的毒性（圖1）[28-29]。其次，茶多酚還可以作用于已形成的淀粉樣纖維，如EGCG可以附著于淀粉樣纖維的表面，在硫黃素淀粉顯色試驗(yàn)中，可與硫黃素競爭結(jié)合淀粉樣纖維可結(jié)合的位點(diǎn)，減少硫黃素與纖維的結(jié)合，并推斷EGCG可能通過與纖維表面的氨基酸作用，形成非晶體蛋白質(zhì)，減少對(duì)細(xì)胞的毒性[27]。

另一類影響AD發(fā)生的蛋白是tau蛋白，“tau蛋白假說”認(rèn)為tau蛋白作為一類微管結(jié)合蛋白，用以穩(wěn)定微管，保持神經(jīng)元的正常運(yùn)轉(zhuǎn)。在岡田酸誘導(dǎo)的急性記憶和學(xué)習(xí)損傷大鼠模型中，發(fā)現(xiàn)茶多酚可以使磷酸化的tau蛋白相應(yīng)減少[30]。Heike J W 等[31]通過在體外培養(yǎng)tau蛋白片段（His-K18DK280）模擬AD發(fā)病機(jī)制，發(fā)現(xiàn)EGCG可以抑制tau蛋白片段聚合成有毒性的低聚體，其原理與EGCG作用于Aβ的不同，而是歸結(jié)于EGCG可以和錯(cuò)誤折疊的tau蛋白單體結(jié)合，結(jié)合了EGCG的錯(cuò)誤折疊單體可以轉(zhuǎn)換回其未折疊的單體或非激活形式，抑制其進(jìn)一步聚集，該作用類似于分子伴侶蛋白（圖2）。

2.2 防止氧化應(yīng)激

引起腦內(nèi)氧化應(yīng)激的因素主要包括線粒體功能障礙、異常蛋白誘導(dǎo)及膠質(zhì)細(xì)胞的激活3類，其中線粒體電子傳遞異常產(chǎn)生的活性氧構(gòu)成了腦內(nèi)自由基的主體。對(duì)于再生能力有限且耗能較多的神經(jīng)元來說，更容易積累氧化損傷[32]。

茶多酚具有優(yōu)異的抗氧化性能，EGCG可以使從AD模型小鼠的海馬、皮質(zhì)和紋狀體中分離出的線粒體產(chǎn)生呼吸率、膜電位、活性氧，以及使ATP水平恢復(fù)50%~85%[33]。在SAMP10小鼠試驗(yàn)中，發(fā)現(xiàn)綠茶兒茶素可以抑制DNA氧化損傷產(chǎn)物8-羥化脫氧鳥苷（8-hydroxy-2' -deoxyguanosine，8-OHdG）的合成[34]。通過攝食1個(gè)月的兒茶素，老年大鼠紋狀體和中腦線粒體碎片中的超氧化物歧化酶（Superoxide dismutase，SOD）活性顯著上升，皮層和小腦中脂質(zhì)過氧化形成的硫代巴比妥酸反應(yīng)物減少[35]。在SAMP10小鼠模型中，綠茶兒茶素可以恢復(fù)谷胱甘肽過氧化物酶（Glutathione peroxidase，GPx）活性，同時(shí)羰基化蛋白質(zhì)含量下降[36]。在C57BL/6J老年小鼠中，兒茶素可以通過抑制血清中SOD、GPx活性的降低，降低海馬部硫代巴比妥酸反應(yīng)物和羰基化蛋白質(zhì)的含量，從而防止腦老化[37]。但是，較高濃度的茶多酚會(huì)產(chǎn)生反向作用，如高濃度的EGCG會(huì)減弱一些抗氧化酶的活性，如SOD、血紅素氧合酶1（Heme Oxygenase-1, HO-1）、NAD(P)H：醌氧化還原酶1和過氧化氫酶[38-39]。

2.3 調(diào)節(jié)細(xì)胞信號(hào)通路

2.3.1 影響信號(hào)轉(zhuǎn)導(dǎo)通路

茶多酚可以影響細(xì)胞內(nèi)多條關(guān)于細(xì)胞存活/凋亡的信號(hào)通路，目前研究表明它主要可以作用于絲裂原活化蛋白激酶（Mitogen- activated protein kinase，MAPK）、絲氨酸-蘇氨酸蛋白激酶B（AKT/protein kinase B，AKT/PKB）和蛋白激酶C（Protein kinase C，PKC）等信號(hào)級(jí)聯(lián)系統(tǒng)且通過控制目標(biāo)分子的磷酸化水平來影響細(xì)胞功能[19]。

PKC家族在控制記憶力方面發(fā)揮著至關(guān)重要的作用，在神經(jīng)保護(hù)方面起關(guān)鍵作用。EGCG通過激活PKC來抵抗Aβ誘導(dǎo)的細(xì)胞凋亡，在Aβ誘導(dǎo)的PC12和SH-SY5Y毒性細(xì)胞中，EGCG通過作用于PKC信號(hào)通路影響α分泌酶活性，調(diào)控APP的加工，而這一效應(yīng)可以被α分泌酶和PKC的抑制劑Ro31-979和GF109203X所消除。連續(xù)2周服用EGCG（2?mg·kg-1），雄性C57/BL小鼠紋狀體中PKCα及海馬部PKCα和PKC?的表達(dá)顯著增加[40]。AKT作為強(qiáng)有力的Bad激酶，活化的AKT可以使Bad蛋白的Ser136位點(diǎn)磷酸化，磷酸化的Bad能與伴侶蛋白14-3-3 gamma結(jié)合，從而阻斷Bad與Bcl-2或Bcl-xL蛋白形成二聚體，使Bad不能發(fā)揮促細(xì)胞凋亡的作用[41]。在大鼠原代培養(yǎng)的前額葉皮層神經(jīng)元中，茶多酚可以顯著抑制由Aβ誘導(dǎo)的磷酸化AKT表達(dá)的下降[42]。MAPK通路也在神經(jīng)元保護(hù)和分化生長方面起關(guān)鍵作用，MAPK通路中的蛋白激酶通?？煞譃閮纱箢?，細(xì)胞外信號(hào)調(diào)節(jié)激酶（Extracellular signal-regulated kinases，ERK），一般被生長因子和有絲分裂原激活，而p38蛋白激酶和c-Jun氨基末端激酶（c-jun-N-terminal kinase，JNK）的激活則源于應(yīng)激反應(yīng)，抗細(xì)胞凋亡[43-44]。EGCG具有激活所有MAPK激酶的潛在活性，且與時(shí)間、劑量相關(guān)，而EGC可以激活ERK和p38。EGCG使MAPK信號(hào)通路激酶達(dá)到最高活性的時(shí)間較快，約為2?h，而激活caspase-3則需較長時(shí)間，峰值出現(xiàn)在16?h，因此高濃度EGCG持續(xù)激活MAPK信號(hào)通路可能引發(fā)對(duì)其他通路如caspases的激活而導(dǎo)致細(xì)胞凋亡[45]。然而，研究也發(fā)現(xiàn)在神經(jīng)細(xì)胞株和初級(jí)神經(jīng)元的培養(yǎng)中，無論是EGCG還是C，在它們能起到神經(jīng)保護(hù)的濃度條件下（1~10?μmol·L-1），如果沒有外源性損傷，均不能影響ERK或AKT的磷酸化水平[43]。

2.3.2 調(diào)節(jié)凋亡因子

目前調(diào)控細(xì)胞凋亡研究最為深入的是bcl-2家族基因，bcl-2家族基因通常抑制細(xì)胞凋亡，然而其組分bax基因則促進(jìn)凋亡。bax基因編碼的Bax蛋白，作為胞質(zhì)蛋白，容易易位到線粒體外膜上，影響膜滲透性和細(xì)胞色素C的釋放，受p53基因的激活[46]。因此bcl-2/bax基因的比值通常是衡量細(xì)胞存活/凋亡的重要參照物。在SH-SY5Y細(xì)胞中，通過茶多酚的預(yù)處理可以增加bcl-2 mRNA的表達(dá)水平，降低bax基因的表達(dá)[47]。低濃度EGCG水平下，神經(jīng)元細(xì)胞中促凋亡基因bax、bad、p21、gadd45、fas配體及caspase-1和caspase-6的表達(dá)下降，而抗凋亡基因bcl-2家族成員bcl-2和bcl-xl基因的表達(dá)基本未受到EGCG的影響，表明EGCG發(fā)揮神經(jīng)保護(hù)作用是通過下調(diào)促細(xì)胞凋亡基因的表達(dá)實(shí)現(xiàn)的[48-49]。在培養(yǎng)的大鼠皮層神經(jīng)元細(xì)胞模型中，相對(duì)于UV-C造成的細(xì)胞凋亡，茶多酚可以明顯抑制bax基因的表達(dá)，而在已用UV-C處理的受損細(xì)胞中，茶多酚則不能發(fā)揮其保護(hù)作用[46]。EGCG可以抑制1-甲基-4-苯基-1,2,3,6-四氫吡啶（1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine，MPTP）誘導(dǎo)的小鼠海馬部Bax蛋白表達(dá)的上調(diào)，阻止Bcl-2蛋白表達(dá)的下降[50]。在大鼠PC12細(xì)胞中，綠茶提取物可以抑制由Aβ25–35引發(fā)的促凋亡基因p53、bax及caspase-3水平的上升，阻止ERK和p38的激活[51]。

2.4 調(diào)節(jié)神經(jīng)遞質(zhì)水平

2.4.1 抗膽堿能活性

“膽堿能假說”認(rèn)為，AD的發(fā)生與神經(jīng)遞質(zhì)乙酰膽堿（Acetylcholine，ACh）的合成減少有關(guān)。釋放到突觸間隙中的ACh在乙酰膽堿酯酶（Acetylcholinesterase，AChE）的作用下水解產(chǎn)生膽堿，影響ACh的利用度，因此抑制AChE活性具有重要意義[52]。在雄性ICR小鼠試驗(yàn)中證實(shí)，茶多酚的抗膽堿能活性與認(rèn)知功能提高、學(xué)習(xí)和記憶力提高相關(guān)[53]。在Wistar雄性大鼠腦室里注入鏈脲霉素形成的慢性腦功能障礙模型中，EGCG可以顯著降低AChE的活性[54]。綠茶提取物抑制AChE的活性呈劑量依賴關(guān)系，其IC50為42.05?μg·mL-1，效果優(yōu)于毒扁豆堿[55]。在人神經(jīng)上皮瘤細(xì)胞SK-N-MC中發(fā)現(xiàn)茶多酚抑制AChE活性的IC50是248?μg·mL-1 [47]。

2.4.2 抑制興奮性神經(jīng)毒性

興奮性神經(jīng)遞質(zhì)過度釋放也為誘導(dǎo)AD發(fā)生的重要因素。在胎鼠大腦皮層神經(jīng)元細(xì)胞中，對(duì)于谷氨酸誘導(dǎo)的神經(jīng)毒性，兒茶素對(duì)Ca2+超載影響不大，卻可以顯著抑制caspase-3的活性[56]。皮層神經(jīng)元長期暴露于Aβ會(huì)積累大量ROS，導(dǎo)致NMDA受體活性減弱，這一效應(yīng)同樣可以被EGCG改善[57]。另外在老年小鼠的海馬部同樣發(fā)現(xiàn)突觸后膜NMDA受體水平顯著下降，長期攝入綠茶兒茶素可以防止老年化導(dǎo)致的NMDA受體的減少[37]。

2.5 抗炎

錯(cuò)誤折疊的蛋白可作為催化劑使膠質(zhì)細(xì)胞激活，引發(fā)炎癥。流行病研究發(fā)現(xiàn)，AD患者通過服用非甾體抗炎藥，可在一定程度上抑制AD的發(fā)病[58]。茶多酚可以調(diào)節(jié)炎癥相關(guān)信號(hào)通路，如可抑制核轉(zhuǎn)錄因子（Nuclear factor kappaB，NF-κB）的激活。NF-κB通常以非活化的形式貯存在胞漿，由3種亞基組成：p50、p65和IκB。當(dāng)IκB與p50、p65結(jié)合時(shí)，NF-κB處于非活化形態(tài)，IκB的磷酸化使其從p50、p65上脫落下來，NF-κB得以激活[59]。C57BL/6J老年小鼠試驗(yàn)中發(fā)現(xiàn)，攝入綠茶兒茶素可以降低海馬CA1區(qū)NF-κB的表達(dá)[37]。在PC12細(xì)胞中，Lee等[51]發(fā)現(xiàn)Aβ25-35可以使胞漿中磷酸化的IκB表達(dá)增強(qiáng)，但是這一效果會(huì)被綠茶提取物所阻礙。在小鼠的海馬區(qū)，EGCG可以顯著抑制次聲波導(dǎo)致的小膠質(zhì)細(xì)胞的激活，表現(xiàn)為白細(xì)胞介素-1β（Interleukin-1β，IL-1β），IL-6、IL-18和腫瘤壞死因子（Tumor necrosis factor，TNF-α）表達(dá)的下降，同時(shí)減弱IκBα的磷酸化[60]。在脂多糖誘導(dǎo)的AD模型ICR小鼠中，口服EGCG（1.5?mg·kg-1和3?mg·kg-1）水溶液預(yù)處理可以抑制星形膠質(zhì)細(xì)胞的激活，TNF-α、IL-1β、IL-16的表達(dá)也有所下降[61]。

2.6 保護(hù)端粒

端粒是真核生物染色體末端的一種特殊結(jié)構(gòu)，伴隨細(xì)胞分裂，端粒長度逐漸縮短，當(dāng)復(fù)制到一定數(shù)量時(shí)，細(xì)胞衰老，復(fù)制能力下降。已有很多研究表明，與衰老相關(guān)疾?。ㄈ鏏D）的發(fā)生與端粒的長度呈負(fù)相關(guān)[62-64]，健康的生活方式與端粒的長度呈正相關(guān)，炎癥、氧化應(yīng)激、心理壓力等都會(huì)影響端粒的長度[65]。研究顯示，在外周血細(xì)胞中，習(xí)慣飲茶受試者的端粒長度要長于不經(jīng)常飲茶的人，可能與茶多酚的抗炎效果有關(guān)[21]。在心肌肥大的大鼠心肌細(xì)胞中，EGCG和槲皮素都會(huì)抑制端粒的縮短和氧化應(yīng)激[66]。

3 展望

茶多酚可以有效改善AD病情已在體外和動(dòng)物試驗(yàn)中得到證實(shí)，主要通過抑制異常蛋白積累、抗氧化應(yīng)激、調(diào)節(jié)細(xì)胞信號(hào)通路及抗炎等。但是目前解釋AD發(fā)病機(jī)制的假說都不夠全面，如“淀粉樣蛋白假說”認(rèn)為腦中Aβ的積累構(gòu)成了AD發(fā)病的關(guān)鍵因素，但老年斑、神經(jīng)細(xì)胞及突觸數(shù)量的減少也可見于并無癡呆癥狀的正常老年人，只是程度相對(duì)較輕而已。因此如何來衡量影響AD發(fā)病的生物指標(biāo)大小至關(guān)重要，可能發(fā)病前期出現(xiàn)的病理特征會(huì)是可逆的或可延緩的。

目前將茶多酚應(yīng)用于AD的臨床研究仍存在一些問題，血腦屏障及人體吸收代謝的復(fù)雜性使得到達(dá)腦內(nèi)的茶多酚含量及活性受到極大影響。因此，未來可考慮采用各種改性方式幫助茶多酚及其代謝產(chǎn)物在腦中發(fā)揮更好的作用。但是也需注意，高濃度的茶多酚具有潛在的副作用，確定合適的給藥劑量至關(guān)重要。

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Progress in the Prevention of Tea Polyphenols on Alzheimer's Disease and Their Mechanisms

WEI Ran, XU Ping*, YING Le, WANG Yuefei

Department of Tea Science, Zhejiang Univerisity, Hangzhou 310058, China

Alzheimer's disease, a kind of neurodegenerative disease, is caused by the abnormal neurons associated with cognitive function, which can lead to the decline of memory, even affect the independent action and swallow. It has been reported that tea polyphenols showed positive effects on Alzheimer's disease by inhibiting the accumulation of abnormal proteins, antioxidative, modulating neurotransmitter levels, regulating cell signaling pathways and anti-inflammatory, etc. In the present paper, the prevention of tea polyphenols on Alzheimer's disease was summarized, and their mechanisms were discussed as well.

Alzheimer's disease, tea polyphenols, abnormal proteins, neurotransmitter, anti-inflammatory

Q946.84+1

A

1000-369X（2016）01-001-10

2015-08-28

2015-10-20

2013年度公益性行業(yè)科研專項(xiàng)經(jīng)費(fèi)項(xiàng)目（GYHY201306037）

魏然，女，碩士研究生，主要從事茶天然產(chǎn)物與人體健康及其機(jī)理研究。*通訊作者：zdxp@zju.edu.cn