【摘要】：研究背景 阿爾茨海默病(Alzheimer's disease, AD)是一種發(fā)生于中樞神經(jīng)系統(tǒng)的退行性病變,是目前老年人癡呆的最主要類型,至今病因不明。全球范圍內(nèi)約35,000,000人罹患此病。該病特征性表現(xiàn)是進行性記憶力減退和認(rèn)知功能障礙。AD病理學(xué)的特征性改變?yōu)棣?淀粉樣肽(β-amyl oid, Aβ)沉積形成的老年斑,由tau蛋白異常聚集形成的神經(jīng)原纖維纏結(jié),大腦皮層細(xì)胞不同程度的減少,以及星形膠質(zhì)細(xì)胞的增生和肥大。AD原因錯綜復(fù)雜,其中神經(jīng)炎癥機制在阿爾茨海默病的發(fā)生和發(fā)展進程中發(fā)揮了重要作用,Ap沉積激活小膠質(zhì)細(xì)胞引起的炎癥反應(yīng)可能是AD的核心病理機制。TOLL-樣受體(Toll-like recepter, TLR)家族成員可通過識別各種病原體相關(guān)分子模式(pathogen associated molecular pattern,PAMP)引發(fā)機體免疫反應(yīng),一些列研究證實Toll樣受體2(TLR2)可能在AD的神經(jīng)變性機制和病情進程中起到重要的作用。而且,TLR2參與細(xì)胞對AD相關(guān)Aβ的攝取及清除。我們以前的研究已經(jīng)證實TLR2基因改變與AD的遺傳易感風(fēng)險相關(guān)。 在人類,TLR2基因均有許多多態(tài)性位點,他們所在區(qū)域為AD遺傳易感相關(guān)區(qū)域。因此我們首次提出TLR2基因遺傳多態(tài)性可能為AD的遺傳風(fēng)險因子,而外周血單核細(xì)胞TLR2基因和蛋白表達量可能為AD的早期診斷生物標(biāo)志。 方法 本研究采用美國神經(jīng)病學(xué)、語言障礙和卒中研究所-老年性癡呆和相關(guān)疾病學(xué)會(NINCDS—ADRDA)中“很可能AD(probable)"標(biāo)準(zhǔn),選擇LOAD患者60例(年齡≥65歲,民族為漢族,女性33例,平均年齡80.2±8.2歲),并選擇同期就診的60例健康查體者作為對照(女性34例,平均年齡80.6±6.3歲)。所有研究對象均為中國北方漢族人且無親緣關(guān)系。所有入選病人均禁食12小時,抽取清晨空腹血各5.5mLEDTA抗凝,采用實時熒光定量聚合酶鏈反應(yīng)(RT-PCR)技術(shù)、流式細(xì)胞術(shù)、單管雙向等位基因特異性擴增分別對mRNA、血漿蛋白表達進行檢測。使用SPSS11.5統(tǒng)計軟件進行統(tǒng)計分析。病例組和對照組各種特征的比較采用t檢驗或卡方檢驗。多組之間的比較采用單因素方差分析,組間兩兩比較采用Bonferroni法。使用Pearson積矩相關(guān)來評估m(xù)RNA、蛋白與MMSE評分的相關(guān)性。P0.05為差異有統(tǒng)計學(xué)意義。所有統(tǒng)計學(xué)檢驗均為雙側(cè)概率檢驗,以P0.05為差異有統(tǒng)計學(xué)意義的標(biāo)準(zhǔn)。測定研究對象的一般特征,確保兩組研究人員在年齡、性別、BMI、血壓數(shù)值、高密度脂蛋白、低密度脂蛋白、膽固醇、血糖上均無顯著差異。 結(jié)果 結(jié)果發(fā)現(xiàn)和健康對照組相比,病例組中TLR2mRNA的表達均高于對照組(TLR2:0.390±0.204比0.281±0.167,P0.01)。病例組中TLR2的蛋白表達也顯著高于健康對照組(TLR2:97.12±1.67%比41.07±18.44%, P0.01)。且無論在病例組還是健康對照組,TLR2mRNA的表達均與TLR2蛋白的表達顯著相關(guān)(分別為TLR2:r=0.980和0.976,P0.01;)。 結(jié)論 本實驗首次對中國北方漢族人群TLR2在LOAD患者外周血中mRNA和血漿蛋白水平的表達進行研究,LOAD組TLR2mRNA及其蛋白水平明顯增加,而且TLR2mRNA水平與TLR2的蛋白表達有明顯的相關(guān)性,證明中國北方漢族人群TLR基因表達與LOAD易感性有關(guān)。 研究背景 To1l樣受體的研究歷史雖然僅僅20年,但Toll樣受體的發(fā)現(xiàn)開創(chuàng)了我們理解先天免疫細(xì)胞如何識別外源性(即微生物品種)以及內(nèi)源(即機體衍生物)致病分子,隨后引發(fā)炎癥反應(yīng)機制的新紀(jì)元。這些研究提供了先天免疫系統(tǒng)復(fù)興的飛躍。對免疫學(xué)領(lǐng)域的研究發(fā)現(xiàn),在系統(tǒng)發(fā)生上保守的先天性免疫不僅提供了防御微生物入侵的第一道防線,而且還影響組織的損傷反應(yīng),控制適應(yīng)性免疫的活性。 阿爾茨海默氏病(AD)的特征表現(xiàn)是腦皮質(zhì)內(nèi)形成不溶性β-淀粉樣蛋白(Aβ)沉積物。沉積物的形成與小膠質(zhì)細(xì)胞介導(dǎo)的炎性反應(yīng)有關(guān)。近期研究表明Toll-樣受體(Toll-like recepter, TLRs)參與該炎性反應(yīng)。TLR家族成員可通過識別各種病原體相關(guān)分子模式(pathogen associated molecular pattern, PAMP)引發(fā)機體免疫應(yīng),一些列研究證實Toll樣受體4(TLR4)可能在AD的神經(jīng)變性機制和病情進程中起到重要的作用。而且,TLR4參與細(xì)胞對AD相關(guān)Aβ的攝取及清除我們以前的研究已經(jīng)證實TLR4基因改變AD的遺傳易感風(fēng)險相關(guān)。 我們先前的大量研究發(fā)現(xiàn)TLR4基因有許多多態(tài)性遺傳位點,與AD的遺傳易感相關(guān)。因此我們首次提出TLR4基因遺傳多態(tài)性可能為AD的遺傳風(fēng)險因子,而外周血單核細(xì)胞TLR4基因和蛋白表達量可能為AD的早期診斷生物標(biāo)志。 方法 本研究采用美國神經(jīng)病學(xué)、語言障礙和卒中研究所-老年性癡呆和相關(guān)疾病學(xué)會(NINCDS—ADRDA)中“很可能AD(probable)"標(biāo)準(zhǔn),選擇LOAD患者60例(年齡≥65歲,民族為漢族,女性33例,平均年齡80.2±8.2歲),并選擇同期就診的60例健康查體者作為對照(女性34例,平均年齡80.6±6.3歲)。所有研究對象均為中國北方漢族人且無親緣關(guān)系。所有入選病人均禁食12小時,抽取清晨空腹血各5.5mLEDTA抗凝,采用實時熒光定量聚合酶鏈反應(yīng)(RT-PCR)技術(shù)、流式細(xì)胞術(shù)、單管雙向等位基因特異性擴增分別對mRNA、血漿蛋白表達及Toll樣受體4(TLR4)基因3'UTR11367位點的基因多態(tài)性進行檢測。使用SPSS11.5統(tǒng)計軟件進行統(tǒng)計分析。病例組和對照組各種特征的比較采用t檢驗或卡方檢驗。多組之間的比較采用單因素方差分析,組間兩兩比較采用Bonferroni法,P0.05為差異有統(tǒng)計學(xué)意義。所有統(tǒng)計學(xué)檢驗均為雙側(cè)概率檢驗,以P0.05為差異有統(tǒng)計學(xué)意義的標(biāo)準(zhǔn)。測定研究對象的一般特征,確保兩組研究人員在年齡、性別、BMI、血壓數(shù)值、高密度脂蛋白、低密度脂蛋白、膽固醇、血糖上均無顯著差異。 結(jié)果 結(jié)果發(fā)現(xiàn)和健康對照組相比,病例組中TLR4mRNA的表達均高于對照組(TLR4:0.503±0.195比0.322±0.183,P0.01)。病例組中TLR4的蛋白表達也顯著高于健康對照組(TLR4:66.56±23.74%比14.83±4.31,P0.01)。且無論在病例組還是健康對照組,TLR4mRNA的表達與TLR4蛋白的表達顯著相關(guān)(TLR4：r=0.938和0.970,P0.01)。在病例組中,TLR4在基因型為CC中的蛋白表達水平顯著低于在基因型為GG純合子和GC雜合子中的表達水平。而在健康對照組中,TLR4的蛋白表達水平在三種基因型中差異無統(tǒng)計學(xué)意義。 結(jié)論 本實驗首次對中國北方漢族人群TLR4在LOAD患者外周血中mRNA和血漿蛋白水平的表達進行研究,LOAD組TLR4mRNA及其蛋白水平明顯增加,而且TLR4mRNA水平與TLR4的蛋白表達有明顯的相關(guān)性。TLR4基因3’UTR11367基因型CC增加LOAD患者全血TLR4蛋白表達,證明中國北方漢族人群TLR基因表達與LOAD易感性有關(guān)。
[Abstract]:Research background
Alzheimer's disease (AD) is a degenerative disease occurring in the central nervous system. It is the most important type of dementia in the elderly, and the cause of the disease is unknown. About 35000000 people worldwide are suffering from this disease. The characteristic features of this disease are progressive memory impairment and the pathological features of cognitive dysfunction.AD. The changes in the formation of beta amyloid peptide (beta -amyl oid, A beta) in the senile plaques were caused by abnormal aggregation of tau protein, the decrease of cortical cells in varying degrees, and the complicated causes of astrocyte proliferation and hypertrophy of.AD, in which the mechanism of neuritis is in the progression and development of Alzheimer's disease. The important role of Ap deposition in the activation of microglia may be the core pathological mechanism of AD, the.TOLL- like receptor (Toll-like recepter, TLR) family members can induce the immune response by identifying various pathogen related molecular models (pathogen associated molecular pattern, PAMP). Some studies confirm Toll Like receptor 2 (TLR2) may play an important role in the neurodegenerative mechanism and progression of AD. Moreover, TLR2 participates in the uptake and removal of AD related A beta. Our previous study has shown that the TLR2 gene changes are associated with the genetic susceptibility to AD.
In humans, there are a number of polymorphic loci in the TLR2 gene, and their region is a genetic susceptibility region of AD. Therefore, we first proposed that the genetic polymorphism of the TLR2 gene may be a genetic risk factor for AD, and the TLR2 gene and protein expression of peripheral blood mononuclear cells may be a biomarker for the early diagnosis of AD.
Method
This study uses the "very likely AD (probable)" standard in the American neurology, language disorder and Stroke Research Institute of Alzheimer's disease and related diseases (NINCDS - ADRDA) to select 60 cases of LOAD patients (age 65 years old, ethnic Han, female 33, average age 80.2 + 8.2 years old), and select 60 healthy subjects as controls at the same time as control. (34 women, with an average age of 80.6 + 6.3 years old). All the subjects were all the Han people in the north of China and had no relationship. All the selected patients were fasted for 12 hours, taking 5.5mLEDTA anticoagulant in the morning empty blood, using real time fluorescence quantitative polymerase chain reaction (RT-PCR), flow cytometry and single tube bidirectional allele specific amplification, respectively. MRNA, plasma protein expression was detected. SPSS11.5 statistical software was used for statistical analysis. The comparison of the characteristics of the case group and the control group was compared with the t test or the chi square test. The comparison among the groups was compared with the single factor analysis of variance, and the 22 of the groups was compared with the Bonferroni method. The evaluation of mRNA, protein and MMSE was evaluated by the correlation of Pearson moment. The correlation.P0.05 was statistically significant. All statistical tests were both bilateral probability tests and P0.05 as a statistically significant standard. The general characteristics of the subjects were measured to ensure that two groups of researchers were not significant in age, sex, BMI, blood pressure, HDL, LDL, cholesterol, and blood sugar. There is a difference.
Result
The results showed that the expression of TLR2mRNA in the case group was higher than that in the control group (TLR2:0.390 + 0.204 / 0.281 + 0.167, P0.01). The protein expression of TLR2 in the case group was significantly higher than that in the healthy control group (TLR2:97.12 1.67% to 41.07 + 18.44%, P0.01), and the expression of TLR2mRNA in both the case group and the healthy control group was all with TLR2. Protein expression was significantly correlated (TLR2:r=0.980 and 0.976, P0.01, respectively).
conclusion
In this experiment, the expression of mRNA and plasma protein levels in peripheral blood of LOAD patients in northern Han population of northern China was studied. The level of TLR2mRNA and its protein in group LOAD was significantly increased, and the level of TLR2mRNA was significantly correlated with the protein expression of TLR2. It was proved that the expression of TLR gene in the Han population in northern China was related to the susceptibility to LOAD.
Research background
The history of the To1l like receptor is only 20 years old, but the discovery of Toll like receptors opens up a new era in understanding how innate immune cells identify exogenous (i.e. microbial species) and endogenous (organism derivatives) pathogenic molecules and subsequently trigger the mechanism of inflammation. These studies provide a leap in the revival of the innate immune system. Studies in the field of immunology have found that conserved innate immunity in the system not only provides the first line of defense against microbial invasion, but also affects the tissue damage response and controls the activity of adaptive immunity.
The characteristics of AD are characterized by the formation of insoluble beta amyloid (A beta) deposits in the cortex. The formation of the sediments is associated with the microglia mediated inflammatory response. Recent studies have shown that the Toll- like receptor (Toll-like recepter, TLRs) participates in the inflammatory response of the.TLR family members by identifying various pathogens. Pathogen associated molecular pattern (PAMP) triggers the immune response to the body. Some column studies have confirmed that Toll like receptor 4 (TLR4) may play an important role in the neurodegenerative mechanism and progression of AD. Moreover, TLR4 participation in the uptake and clearance of AD related A beta has been confirmed by our previous study of TLR4 genes. The risk of genetic susceptibility is related.
A number of previous studies have found that the TLR4 gene has a number of polymorphic loci and is associated with the genetic susceptibility to AD. Therefore, we first proposed that the genetic polymorphism of the TLR4 gene may be a genetic risk factor for AD, and the expression of TLR4 gene and protein in peripheral blood mononuclear cells may be an early diagnostic biomarker of AD.
Method
This study uses the "very likely AD (probable)" standard in the American neurology, language disorder and Stroke Research Institute of Alzheimer's disease and related diseases (NINCDS - ADRDA) to select 60 cases of LOAD patients (age 65 years old, ethnic Han, female 33, average age 80.2 + 8.2 years old), and select 60 healthy subjects as controls at the same time as control. (34 women, with an average age of 80.6 + 6.3 years old). All the subjects were all the Han people in the north of China and had no relationship. All the selected patients were fasted for 12 hours, taking 5.5mLEDTA anticoagulant in the morning empty blood, using real time fluorescence quantitative polymerase chain reaction (RT-PCR), flow cytometry and single tube bidirectional allele specific amplification, respectively. MRNA, plasma protein expression and Toll like receptor 4 (TLR4) gene locus 3'UTR11367 polymorphism were detected. Statistical analysis was performed using SPSS11.5 software. The comparison of the characteristics of the case group and the control group was compared with the t test or chi square test. The comparison between the groups was compared with the single factor analysis of variance, and the 22 of the groups was compared to Bonferro. The Ni method and P0.05 were statistically significant. All statistical tests were both bilateral probability tests, with P0.05 as a statistically significant standard. The general characteristics of the subjects were measured to ensure that two groups of researchers had no significant differences in age, sex, BMI, blood pressure, HDL, LDL, cholesterol, and blood sugar.
Result
The results showed that the expression of TLR4mRNA in the case group was higher than that in the control group (TLR4:0.503 + 0.195 / 0.322 + 0.183, P0.01). The protein expression of TLR4 in the case group was also significantly higher than that in the healthy control group (TLR4:66.56 23.74% to 14.83 + 4.31, P0.01). The expression of TLR4mRNA and TLR4 eggs in the case group and the healthy control group were also significantly higher than that in the healthy control group. The expression of white was significantly correlated (TLR4:r=0.938 and 0.970, P0.01). In the case group, the expression level of TLR4 in the genotype CC was significantly lower than that in the genotype GG homozygote and GC heterozygote. In the healthy control group, the protein expression level of TLR4 was not statistically significant in the three genotypes.
conclusion
This experiment was the first time to study the expression of mRNA and plasma protein in peripheral blood of patients with LOAD in the Han population of northern China. The level of TLR4mRNA and its protein in group LOAD increased significantly, and the level of TLR4mRNA was significantly correlated with the protein expression of TLR4..TLR4 gene 3 'UTR11367 genotype increased the expression of whole blood TLR4 protein in LOAD patients. It is proved that the expression of TLR gene is related to LOAD susceptibility in Han population of northern China.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R749.16

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