Tau蛋白与阿尔茨海默病关系研究进展

阿尔茨海默病(Alzheimer's disease,AD)是一种以进行性痴呆(记忆减退、认知障碍以及人格改变1为临床特征,大脑皮质和海马区域出现细胞外老年斑、细胞内神经元纤维缠结(neurofibrillary tangle,NFT)和营养不良性轴突改变为病理特征的神经变性疾病[1],并且其痴呆症状的严重程度与NFT的多少有关[2].     

阿尔茨海默病精神行为障碍与载脂蛋白E基因研究

目的：了解阿尔茨海默病（AD）精神行为障碍的临床特征以及与载脂蛋白E（ApoE）基因多态性的相关性。方法：共收集AD患者48例,正常对照者50例,采用阿尔茨海默病行为病理评定量表（BEHAVE-AD）进行精神行为测评,用聚合酶链反应法（PCR）进行ApoE基因分型。结果：AD患者在偏执和妄想、幻觉、行为紊乱和攻击行为方面与正常对照组比较差异有显著性;而ApoE基因检查结果显示携带ApoE ε4基因的AD患者精神行为障碍更为明显。结论：ApoE ε4是AD的风险基因,对携带有ApoE ε4的AD患者应早期干预和治疗。     

阿尔茨海默病患者脑脊液中Tau蛋白的含量及意义

目的：Ａｌｚｈｅｉｍｅｒ病（ＡＤ）实验室诊断指标测定。方法：ＥＬＩＳＡ测定４０例ＡＤ患者,２６例梗塞性痴呆（ＭＩＤ）患者,５８例正常人脑脊液Ｔａｕ含量。结果ＡＤ患者、ＭＩＤ患者脑脊液Ｔａｕ 蛋白含量均明显高于正常对照组（Ｐ＜０．００１）,而ＡＤ组与ＭＩＤ组差别无统计意义（Ｐ＞０．０５）。ＡＤ组Ｔａｕ蛋白含量与病程呈正相关关系（Ｐ＜０．０１,ｒ＝０．４４）,ＭＩＤ组未发现此相关关系（Ｐ＞０．ｌ）．三组测定值与年龄均无相关关系。结论：Ｔａｕ蛋白含量在 ＡＤ患者脑脊液中明显升高,在 ＭＩＤ组亦增高,故单纯测定Ｔａｕ蛋白难以鉴别ＡＤ和ＭＩＤ。作者单位：卫生部课题资助基金（批准编号：９４－１－２４６,卫生部九五攻关课题）     

Tau蛋白与Alzheimer病

1 Tau的分子生物学 Tau蛋白由17号染色体长臂上的单基因编码,经可变剪接产生6种同型。成人脑可表达tau的6种异构,分别由352～441个不等的氨基酸构成,tau羧基末端可见1个重复片段,内含3～4个相同的氨基酸重复序列,每个序列由31～32个氨基酸残基组成。氨基末端含有1个29～58个氨基酸残基的插入序列,CSFtau蛋白形成不同的异构体。外周神经系统主要表达较大的tau异构体,其氨基末端插入254个氨     

阿尔茨海默病患者载脂蛋白E基因启动子区多态性研究

载脂蛋白E(ApoE)基因与阿尔茨海默病(Alzheimer disease，AD)关系密切。在ApoE基因的启动子区存在着多个位点的多态性，由于这些位点距ApoE基因编码区非常近。因而其多态性可能与AD的发病有关。为此我们对启动子区-491A／T。-427T／C两位点多态性与AD的关系进行了研究。     

蒙古族Alzheimer病患者载脂蛋白E基因多态性研究

目的探讨载脂蛋白E(ApoE)基因多态性与蒙古族Alzheimer病(AD)的关系。方法用聚合酶链反应及基因测序技术检测106例蒙古族AD患者和100名正常对照者的ApoE基因的基因型和等位基因频率,并进行比较。结果 AD组中有ApoEε4基因型频率(31.1%)显著高于正常对照组(17.0%)(χ2=5.591,P=0.018;OR=2.207,95%CI:1.136～4.289);ε4等位基因的频率显著高于正常对照组(χ2=4.27,P=0.039;OR=1.841,95%CI:1.026～3.304);两组ApoEε2、ε3等位基因频率的差异无统计学意义。结论ApoE基因ε4等位基因可能是蒙古族人群患AD的遗传性危险因素。     

载脂蛋白E基因多态性与Alzheimer病

目的：探讨广东地区Ａｌｚｈｅｉｍｅｒ病（ＡＤ）患者与ａｐｏＥε４之间的关联性及性别的影响。方法：应用聚合酶链反应－限制性片段长度多态性分析（ＰＣＲ－ＲＦＬＰ）的技术对４４例晚发性散发性ＡＤ患者、３７例非痴呆老年人的ａｐｏＥ基因进行分型。结果：ａｐｏＥε４与晚发性ＡＤ有显著的关联;携带１个或１个以上ε４者与无ε４携带者比较,相对危险度（ＯＲ值）为４．０８,且随ε４基因剂量增加,ＡＤ的患病率上升,发病年龄明显提前（Ｐ＜０．０１）;ＡＤ患者不同性别之间ａｐｏＥε４基因型频率和等位基因频率无显著性差异（Ｐ＞０．０５）。结论ａｐｏＥε４是晚发性ＡＤ发病的危险因素;ＡＤ患者的性别因素与ａｐｏＥε４无相关性。     

载脂蛋白E基因多态性与脑出血关系的Meta分析

OBJECTIVE： To evaluate the relationship between apolipoprotein E （ApoE） gene polymorphism and susceptibility to intracerebral hemorrhage （ICH） in Chinese population by a meta-analysis.
METHODS： Related literature regarding control analysis between ICH and control groups was collected. Independent case-control studies published between 1989 and 2007 that had complete data were included; and articles not closely related to the topic were excluded. The meta-analysis software, RevMan 4.2, was applied to analyze the odds ratio （OR） value in those studies included in the analysis to assess the relationship between susceptibility to ICH and ApoE polymorphism.
RESULTS： Eight papers which were in accordance with the inclusion criteria were selected, and a total of 1 249 ICH cases and 1 329 controls were involved. Meta-analysis results showed that with the wildtype E3/3 as a reference, the OR values （95% confidence interval） of intracerebral hemorrhage for subjects carrying E2/2, E3/2, E4/2, E4/3, and E4/4 were 1.15 （0.60–2.21）, 1.00 （0.79–1.28）, 3.01 （1.73–5.23）, 1.78 （1.41–2.24） and 1.94 （1.03–3.65）, respectively. The combined OR values （95% confidence interval） of intracerebral hemorrhage for ε4 and ε2 carriers were 1.53 （1.16–2.01）, and 0.93 （0.69–1.25）.
CONCLUSION： The results suggest that ApoE polymorphism is significantly associated with susceptibility to intracerebral hemorrhage and that ε4 carriers have a higher risk for intracerebral hemorrhage than others.     

阿尔茨海默病载脂蛋白E基因多态性研究

目的：探讨载脂蛋白E(APoE)基因与阿尔茨海默病(AD)的行为和精神症状之间的关系。方法：采用聚合酶链式反应(PCR)扩增技术和限制性片段长度多态性(RFLP)技术测定85例AD病人的APOE基因多态性；采用AD病理行为量表评定病人的行为和精神症状。结果：对各等位基因及基因型频率分布在有无某项痴呆的行为和精神症状(BPSD)之间进行比较，发现具有行为紊乱症状的病人的ε2等位基因频率分布显著高于无行为紊乱症状的病人；无焦虑和恐惧病人的ε2等位基因频率分布显著高于有症状的病人。AD病人伴有BPSD症状及其严重程度，各基因型之间差异均无显著性。结论：ε2等位基因可能与行为紊乱、焦虑和恐惧症状有一定关联，而APoE基因与阿尔茨海默病的其它行为和精神症状之间未发现关联。     

Alzheimer病患者载脂蛋白E基因多态性及线粒体DAN4336突变的研究

目的　研究散发性Alzheimer病 (AD)患者载脂蛋白E (ApoE)基因型的分布以及线粒体DAN4 336基因突变情况 ,并对不同国家和地区AD患者ApoE基因型的分布频率进行对比。方法　采用聚合酶链反应 限制性片段长度多态性分析 (PCR RFLP)方法对 12 7例AD患者 (AD组 )和 138名正常老年人 (正常组 )ApoE基因型和mtDNA基因突变进行分析。结果　AD组携带 2个、1个和不含ApoE 4基因型的比例为 2 4 %、18 1%和 79 5 % ;正常组的比例分别为 0 7%、10 1%和 89 2 % ,两组比较差异有显著性 (P <0 0 5 ) ;两组均未出现mtDNA 4 336基因突变。AD组ε4 /4比例相对于西方研究报道要低 ,与部分亚洲国家研究相近。结论　ApoE 4等位基因可能是中国散发性AD发生的危险因素 ,ApoE基因型分布频率可能与人群选择、病例分辨和种族、地区差异有关。     

Alzheimer病早期脑脊液tau蛋白与ApoE基因的关系

目的探讨Alzheimer病患者脑脊液tau蛋白与ApoE基因型的关系。方法对84例患者脑脊液微管相关蛋白(tau蛋白)应用ELISA法对进行定量,其中41例临床诊断为早期Alzheimer病(AD),23例伴其他类型的痴呆,6例为Down综合征患者;14例非痴呆患者为对照组。结果多变量ANOVA分析显示痴呆患者与ApoE等位基因者脑脊液tau蛋白升高,AD患者脑脊液tau蛋白浓度明显高于对照组。而非AD痴呆患者脑脊液tau蛋白浓度与AD患者和对照组无明显差异,伴ApoEε4等位基因的AD病人与不伴ε4等位基因的AD病人相比,tau蛋白浓度升高。结论脑脊液tau蛋白浓度升高提示携带ε4等位基因AD病人早期发生神经变性和神经纤维病理学改变,应用ELISA法检测脑脊液tau蛋白对诊断早期AD及与其他类型的痴呆相鉴别缺乏敏感性和特异性,应首先考虑ApoE基因类型。     

载脂蛋白E基因多态性和脑出血关系的研究

目的:探讨载脂蛋白E基因(ApoE)多态性与脑出血的相关关系。方法:采用病例-对照研究,对313例脑出血患者和351例正常对照组进行研究。采用聚合酶链式反应-限制性片段长度多态性方法测定ApoE基因多态性。结果:脑出血组ApoE基因型频率E3/3、E3/4、E3/2、E2/4、E4/4和E2/2型分别为69.0％、15.00％、11.5％、2.9％、1.0％、0.6％。ApoE各基因型和等位基因频率在脑出血组和对照组之间无显著性差异(P>0.05)。结论:研究未发现ApoE基因多态性与脑出血之间存在相关关系     

载脂蛋白E基因多态性与血管性痴呆的关系

目的探讨载脂蛋白E(ApoE)基因多态性与血管性痴呆的关系,并分析其可能的作用机制。方法应用聚合酶链反应-限制性片段长度多态性技术,检测65例血管性痴呆患者(血管性痴呆组)和120名健康受试者(对照组)的ApoE基因型和基因频率;同时对血清总胆固醇、甘油三酯、低密度脂蛋白和高密度脂蛋白进行检测,分析ApoE基因多态性对血脂代谢的影响。结果血管性痴呆组与对照组均以ε3/3基因型出现频率最高,但血管性痴呆组患者的ε4基因出现频率(14.6%)显著高于对照组(4.6%,P<0.01)。血管性痴呆组血清总胆固醇水平明显高于对照组(P<0.05)。在血管性痴呆组,ε4基因具有升高血清总胆固醇水平的作用;而在正常对照组,ε2基因具有降低血清甘油三酯和低密度脂蛋白水平的作用,说明ε4基因与血清总胆固醇水平升高具有相关性。结论ApoEε4是血管性痴呆发病的的遗传易感因子;血管性痴呆患者存在血脂代谢紊乱,且受ApoE基因的调控,ApoE基因可能通过引起血脂代谢紊乱而增加血管性痴呆发病危险性。     

Association between apolipoprotein E genotype and Alzheimer disease in African American subjects

BACKGROUND: The association between Alzheimer disease (AD) and genotypes at the apolipoprotein E (APOE) locus has been confirmed in numerous populations worldwide, but appears to be inconsistent in African American subjects. OBJECTIVE: To investigate the association between APOE genotypes and AD in elderly African American subjects. DESIGN: Clinic-based, multicenter case-control study and a family study. PARTICIPANTS: A total of 338 African American probands meeting criteria for probable or definite AD, 301 cognitively healthy, elderly unrelated control subjects (spouses and community volunteers), and 108 siblings of 88 AD probands. MAIN OUTCOME MEASURES: Odds of AD according to APOE genotype. RESULTS: Compared with individuals with the APOEepsilon3/epsilon3, the odds of having AD were significantly increased among those with 1 or more copies of the epsilon4 allele; the odds ratio (OR) for the epsilon3/epsilon4 genotype was 2.6 (95% confidence interval [CI], 1.8-3.7), and the OR for the epsilon4/epsilon4 genotype was 10.5 (95% CI, 5.1-21.8). These risks decreased substantially after 68 years of age. The risk for AD was lower among individuals with the epsilon2/epsilon3 genotype (OR, 0.41; 95% CI, 0.22-0.79). The patterns of association were similar in men and women. These results obtained from comparisons of unrelated AD patients and controls were bolstered by results of analysis of family data that showed preferential transmission of the epsilon4 allele to demented siblings (P<.001) and of the epsilon2 allele to nondemented siblings (P=.005). CONCLUSIONS: The presence of 1 or 2 epsilon4 alleles is a determinant of AD risk in African American subjects. The age-related risk for decline associated with the epsilon4 allele and the apparent protective effect of the epsilon2 allele are similar to patterns observed in white subjects.     

上海市社区人群阿尔茨海默病与载脂蛋白E基因的关联分析

目的探讨上海地区社区老年人群中阿尔茨海默病(AD)与载脂蛋白E(ApoE)ε     

载脂蛋白E,5—羟色胺转运体基因多态性与阿尔茨海默病的关 …

目的 探索载脂蛋白Ｅ（ａｐｏＥ）基因及５－羟色胺（５－ＨＴ）转运体基因多态性在阿尔茨海默病（ＡＤ）发病中的作用。方法 应用聚合酶链反应（ＰＣＲ）和限制性片段长度多态性方法,观察１０２例ＡＤ和１０５名正常对照组（对照组）的ａｐｏＥ基因多态性及２个５－ＨＴ转运体基因多态性的分布。结果 中,重度ＡＤ患者含ａｐｏＥ ε４基因型频率（２４％）高于对照组（１２％）,但差异无显著性（Ｘ＾２＝３．１７,Ｐ〈０．０     

新疆维吾尔族、汉族载脂蛋白E基因及尿激酶型纤溶酶原激活因子基因多态性与Alzhemier病的关系

目的 探讨新疆维吾尔族(维族)、汉族载脂蛋白E( ApoE)基因及尿激酶型纤溶酶原激活因子( PLAU)基因多态性与Alzheimer's病(AD)的关系.方法 应用PCR-限制性片段长度多态性(RFLP)方法,检测209例很可能AD患者(AD组,汉族98例,维族111例)及220名正常对照者(NC组,汉族103人,维族117人)的ApoE基因及PLAU基因第6号外显子r2227564s基因型及等位基因频率.结果 AD组中,维族、汉族ApoE ε3/4基因型及ε4等位基因频率明显高于NC组;其与PLAU基因C/T基因型组合的频率明显高于NC组(均P＜0.05);具有ApoE ε3/3基因型的维族T/T基因型频率明显高于NC组(P＜0.05).结论 ApoE基因多态性可能与AD相关;PLAU C/T基因型可能增加具有ApoE ε3/4基因型及ε4等位基因者AD的发病风险;PLAU T/T基因型可能增加具有ApoE ε3/3基因型、ε3等位基因的维族AD的发病风险.     

tau 蛋白在阿尔茨海默病中的病理生理机制及 tau 示踪剂研究现状

随着社会人口老龄化,老年性痴呆的患病率逐年增加,已成为继心血管疾病和肿瘤后第三大危及人类生命健康的疾病。通过近二、三十年来对阿尔茨海默病（A D ）的深入研究,已明确了细胞外淀粉样老年斑（Senile Plaques ,SP ）和细胞内神经原纤维缠结（Neurofibrillary Tangles ,NFTs）是AD患者脑中最经典的组织病理变化,也是AD区别于其他痴呆最显著的特征。尸解研究显示,大脑皮质过度磷酸化tau的密度与生前认知障碍及神经元丢失的病理改变明确相关［1］,tau异常是神经退行性变的主要介质,由于匹兹堡化合物B （Pittsburgh Compound B , PiB）对淀粉样蛋白β（Amyloid β,Aβ）的成像成功地用于临床,促进了世界范围内对tau示踪剂及tau成像的纵向研究。目前利用已发现的选择性正电子发射断层扫描（Positron Emission Tomography ,PET ）配体,包括18 F － T HK523,18 F － T HK5105,18 F －T HK5117,18 F － T HK5351,18 F － T807和18 F －T808,进一步确定了 tau蛋白在不同阶段 AD患者脑中的沉积及病理机制,揭示了选择性 tau PET 示踪剂在活体内评估 tau沉积的作用及其与 Aβ的关系［2－4］,tau和 Aβ成像的结合将提高 AD 诊断的特异性,有助于进一步阐明部分认知功能正常个体中无Aβ沉积,但发生AD样神经变性改变的病理学机制［5］,目前认为 tau PET 示踪剂可以作为预测认知功能减退和疾病进展的替代性标记物［6］,对AD和非AD tau病的早期诊断和鉴别诊断具有重要的临床意义。     

Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease

Carriers of the apolipoprotein E (APOE) epsilon4 allele show significantly higher risk of Alzheimer disease (AD). The aim of this present study was to test the hypothesis that a significant interaction exists between APOE genotype and gender on AD. Interactions of epsilon4 by gender, although indicated in the literature, require further verification. A total of 195 past or current control or AD participants in an ongoing longitudinal study of aging and dementia were genotyped. All subjects were at least 60 years old; demented subjects met clinical or pathologic criteria for late-onset AD. Logistic regression analysis and proportional hazard models were used to evaluate joint effects of APOE and gender. A significant statistical interaction between APOE and gender was shown (p = 0.04) in logistic regression analysis. Women carrying one or more APOE-epsilon4 allele were more likely to develop AD [odds ratio (OR) = 7.8, 95% confidence interval (CI) = 3.2-19. 1]. For men, the presence of the APOE-epsilon4 allele was not associated with a statistically significant increased risk (OR = 1.6, 95% CI = 0.5-5.3). The interaction term in the proportional hazards model neared (p = 0.07) statistical significance, and a similar but reduced gender effect was shown. The analysis suggests that the presence of one or more APOE-epsilon4 allele confers a substantially greater risk of AD to women than to men. These findings in part may account for reports of increased risk of AD faced by women.     

Loss of apolipoprotein E receptor LR11 in Alzheimer disease

BACKGROUND: Genetic, epidemiologic, and biochemical evidence suggests that apolipoprotein E, low-density lipoprotein receptors, and lipid metabolism play important roles in sporadic Alzheimer disease (AD). OBJECTIVE: To identify novel candidate genes associated with sporadic AD. DESIGN: We performed an unbiased microarray screen for genes differentially expressed in lymphoblasts of patients with sporadic AD and prioritized 1 gene product for further characterization in AD brain. SETTING: Emory University, Atlanta, Ga. SUBJECTS: Cell lines were used from 14 patients with AD and 9 normal human control subjects. RESULTS: Six genes were differentially expressed in lymphoblasts of 2 independent groups of patients with probable AD and autopsy-proven AD. We hypothesized that 1 of the genes, termed low-density lipoprotein receptor relative with 11 binding repeats (LR11) (reduced 1.8- and 2.5-fold in AD lymphoblasts vs controls), might be associated with sporadic AD on the basis of its function as neuronal apolipoprotein E receptor. We found dramatic and consistent loss of immunocytochemical staining for LR11 in histologically normal-appearing neurons in AD brains. This reduction of LR11 protein was confirmed by quantitative Western blotting (P =.01). CONCLUSIONS: There is loss of the microarray-derived candidate, LR11, in neurons of AD brains. This study shows that microarray analysis of widely available lymphoblasts derived from patients with AD holds promise as a primary screen for candidate genes associated with AD.