本文選題：阿爾茲海默病 + 蛋白磷酸酯酶2A�。� 參考：《華中科技大學(xué)》2012年博士論文

【摘要】：背景：阿爾茨海默病(Alzheimer disease, AD)是一種以進(jìn)行性認(rèn)知障礙和記憶功能損害為主的中樞神經(jīng)系統(tǒng)退行性疾病。主要病理特征是神經(jīng)細(xì)胞外老年斑(senile plaques, SP)沉積和神經(jīng)元內(nèi)神經(jīng)原纖維纏結(jié)(neurofibrillary tangles, NFT)。Alois Alzheimer首先在癡呆病人大腦腦片中發(fā)現(xiàn)：老年斑周圍圍繞著大帚的反應(yīng)性星形膠質(zhì)細(xì)胞。無論在大腦神經(jīng)元發(fā)育還是神經(jīng)退行性變時(shí)均存在星形膠質(zhì)細(xì)胞的遷移。反應(yīng)性星形膠質(zhì)細(xì)胞是如何遷移到老年斑塊周圍的?目前已有大量研究表明蛋白磷酸激酶參與了星形膠質(zhì)細(xì)胞的遷移,而蛋白磷酸酯酶對(duì)星形膠質(zhì)細(xì)胞的遷移作用方面的研究報(bào)道則較少見。 目的：研究蛋白磷酸酯酶-2A(protein phosphatase-2A, PP2A)對(duì)星形膠質(zhì)細(xì)胞遷移的影響并闡述其機(jī)制。 方法：本實(shí)驗(yàn)采用免疫共沉淀(Immunoprecipitation)、免疫印跡(Western blotting)、免疫熒光技術(shù)和PP2A活性試劑盒檢測(cè)AD樣Tg2576轉(zhuǎn)基因鼠腦中星形膠質(zhì)細(xì)胞中PP2A的活性。以體外培養(yǎng)的原代星形膠質(zhì)細(xì)胞為研究模型,采用PP2A特異性抑制劑(OA)或激動(dòng)劑(DES),并結(jié)合脂質(zhì)體和Amax核電轉(zhuǎn)技術(shù)導(dǎo)入外源性DNA,從不同角度分別調(diào)節(jié)PP2A活性,采用細(xì)胞劃痕和Transwell實(shí)驗(yàn)研究PP2A對(duì)細(xì)胞遷移的作用。 結(jié)果：Tg2576轉(zhuǎn)基因鼠中星形膠質(zhì)細(xì)胞內(nèi)PP2A活性增強(qiáng)。在原代培養(yǎng)星形膠質(zhì)細(xì)胞劃痕實(shí)驗(yàn)中,給予PP2A抑制劑OA,及siPP2A抑制PP2A活性后,可抑制星形膠質(zhì)細(xì)胞的遷移,而給予PP2A激活劑DES及轉(zhuǎn)染wtPP2A激活PP2A后,則可促進(jìn)星形膠質(zhì)細(xì)胞的遷移。Transwell小室實(shí)驗(yàn)結(jié)果與劃痕實(shí)驗(yàn)結(jié)果一致。過表達(dá)wtPP2A促進(jìn)星形膠質(zhì)細(xì)胞遷移的同時(shí),無論細(xì)胞胞體還是發(fā)生遷移的偽足,其纖維狀肌動(dòng)蛋白(F-actin)的表達(dá)顯著增高且呈聚集狀態(tài)。給予PP2A激動(dòng)劑DES處理原代星形膠質(zhì)細(xì)胞,結(jié)果發(fā)現(xiàn)激動(dòng)PP2A可下調(diào)磷酸化絲裂原活化蛋白激酶p38MAPK (p38MAPK)水平,而磷酸化c-Jun氨基末端激酶(pJNK)及磷酸化細(xì)胞外調(diào)節(jié)蛋白激酶(pERK)水平無明顯變化,而上調(diào)p38MAPK可部分逆轉(zhuǎn)PP2A所誘導(dǎo)的星形膠質(zhì)細(xì)胞的遷移作用。 結(jié)論：PP2A可通過增加F-actin的聚集和降低p38MAPK活性而促進(jìn)星形膠質(zhì)細(xì)胞的遷移。Tg2576轉(zhuǎn)基因鼠中星形膠質(zhì)細(xì)胞PP2A活性增強(qiáng)促進(jìn)星形膠質(zhì)細(xì)胞遷移到老年斑塊周圍,發(fā)揮其清除Aβ作用。這不僅為星形膠質(zhì)細(xì)胞的遷移提供了新的理論機(jī)制,同時(shí)為通過調(diào)節(jié)星形膠質(zhì)細(xì)胞遷移改善膠質(zhì)病理提供的新的理論基礎(chǔ)。
[Abstract]:BACKGROUND : Alzheimer disease ( AD ) is a degenerative disease of the central nervous system based on progressive cognitive impairment and memory impairment . Alois Alzheimer ' s disease ( Alzheimer ' s disease ) was first found in the brain slices of dementia patients : the presence of reactive astrocytes around the senile plaques around the senile plaques .
Objective : To study the effect of protein phosphatase - 2A ( PP2A ) on the migration of astrocytes and expound its mechanism .
Methods : The activity of PP2A in the brain of AD - like Tg2576 transgenic mice was detected by Immunoptophore , Western blotting , immunofluorescence and PP2A . In vitro , PP2A - specific inhibitor ( OA ) or agonist ( DES ) was used to study the effect of PP2A on the migration of PP2A from different angles .
Results : The activity of PP2A was enhanced in the astrocytes of Tg2576 transgenic mice . After PP2A inhibitor OA was administered and PP2A was inhibited by siPP2A , the migration of astrocytes was inhibited .
Conclusion : PP2A can promote the migration of astrocytes by increasing the aggregation of F - actin and decreasing the activity of p38MAPK .
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R749.16

【引證文獻(xiàn)】

相關(guān)期刊論文 前1條

1 常女子;樊小農(nóng);王曉光;樊同濤;麻聰聰;;中醫(yī)調(diào)控PP2A相關(guān)信號(hào)通路在疾病中的研究進(jìn)展[J];中國(guó)中醫(yī)急癥;2014年07期

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本文編號(hào)：1940687