Tau蛋白介导阿尔兹海默病的机理及相关药物

阿尔兹海默症是一种以智力缓慢丧失为特征的神经退行性疾病,主要病理特征之一为神经细胞内出现大量神经纤维缠结.神经纤维缠结的主要成分为异常磷酸化的Tau蛋白,研究Tau蛋白的结构和功能以及神经纤维缠结形成的分子机制具有重要的生理意义.Tau和Aβ是阿尔兹海默病药物开发的两个重要靶点,随着近期一些以Aβ为靶点的药物临床研究宣告失败,越来越多的研究组已经开始考虑改变研发阿尔兹海默病药物的策略,并开始转向以Tau为靶点的药物开发.本文综述了Tau介导阿尔兹海默病的机理及相关药物的研究进展.     

阿尔兹海默症生物标志物和早期诊断新技术

阿尔兹海默症是当今世界面临的最严重的神经退行性疾病之一.阿尔兹海默症患者的大脑表现出两种主要的神经病理改变:老年斑和神经纤维缠结,其典型临床症状包括记忆丧失、情绪改变、认知能力下降、说话、写作、行走困难等.阿尔兹海默症的早期诊断对通过早期干预策略延缓疾病或改变疾病进程甚至预防疾病都至关重要.该文综述了与阿尔兹海默症相关...     

游离氨基酸对Аβ多肽异常聚集作用的影响

阿尔兹海默氏病的主要病因之一,是病人大脑的海马区和皮质区中Аβ多肽异常聚集形成了老年脑斑.本工作通过质谱方法研究游离氨基酸存在下铜离子和Аβ多肽的相互作用,发现由于其侧链极性和强配位能力,天冬氨酸、谷氨酸、亮氨酸、酪氨酸、苏氨酸和组氨酸6种氨基酸能够在较低浓度下明显抑制铜离子和Аβ多肽的结合,由此推测游离氨基酸可能是一种新的与Аβ多肽异常聚集相关的微环境因素.     

澳大利亚拟禁用6种人造食品色素

不久前,Food Intolerance Network致信澳新食品标准局,呼吁禁止使用6种人造食品色素,这6种色素分别是：晚霞黄（E110）、喹啉黄（E104）、蓝光酸性红（E122）、诱惑红（E129）、酒石黄（E102）、胭脂红（E124）。这些色素用于多种食品中,早先认为与儿童多动症有关系。     

HPO_2异构体结构和相对稳定性

在MP2/6-311++G（d,p）和QCISD（t）/6-311++G（3df,2p）（单点）水平下计算得到了包括8个异构体和12个过渡态的HPO2体系势能面.在势能面上,异构体cis-HOPO（EI）的能量是最低的,其次是trans-HOPO（E2）和HPO（O）（C2v,E3）,能量分别比cis-HOPO高10.99和48.36 kJ/mol.根据体系的势能面,只有异构体E1和E3具有较高的动力学稳定性,在实验中应该可以观测到.PH和O2直接反应生成的cis-HPOO（E5）和trans-HPOO（E6）经过几步势垒较低的异构化过程就可以异构化为具有较高动力学稳定性的产物E1;而OH和PO反应可直接生成E1.计算结果较好地解释了相关实验.     

高硒情况下维生素E对老龄大鼠血清中抗氧化作用的影响

研究了高Se或高维生素E下，老龄大鼠体内抗氧化活性的变化以及高Se下维生素E对其体内抗氧化水平的影响。将十二月龄Wistar大鼠32只随机分成4组：（1）正常饲料组；（2）高Se饲料组；（3）高维生素E饲料组；（4）高Se高维生素E饲料组。饲至十周末，处死大鼠，按试剂盒要求取其血液制成血清测GSH－Px,SOD活性，MDA含量。结果表明，高Se或高维生素E下饲养下的大鼠与对照组比较，血清中GSH－Px活性升高（P＜0．05）。SOD活性未见改变，MDA含量分别减少50％和56％，有显著差异（P＜0．01）；维生素E与高Se合用与高Se组比较能进一步同GSH－Px,SOD活性（P＜0．01）。结论：高Se会升高老龄大鼠的抗氧化活性，而与维生素E合用更加升高老龄大鼠血液中抗氧化活性。     

表面活性剂存在下雌激素的直接电化学分析

雌二醇（E2）、雌三醇（E3）和雌酮（E1）是人体内3种重要的雌激素,它们在妇女的生殖生育方面发挥重要的作用。人体雌激素缺乏或过乘会导致诸多疾病。雌激素的检测方法已有不少报道,如气相色谱－质谱（GC－MS）、液相色谱（LC）以及化学发光免疫法等。E2,E1和E3的结构相似,且均具有疏水性及非电活性,用电化学直接测定十分困难,一般只能间接测定。本文报道了一种新的电化学分析方法。该方法对三种雌激素有十分灵敏的伏安响应,可用于微量测定。     

齐墩果烷型和乌苏烷型五环三萜同分异构体配位色谱法分离机理（英文）

本文主要研究了配位色谱法分离齐墩果烷型和乌苏烷型五环三萜同分异构体的分离机理。基于计算模拟分析,β-环糊精（β-CD）和其衍生物为适宜的配位剂。采用HPLC法测定了包合物的表观形成常数,并制备了asiaticoside-B与β-CD包合物。实验结果显示:流动相中添加葡萄糖基-β-环糊精（Glu-β-CD）时,同分异构体的分离度为11.95,比添加β-CD或添加甲基-β-环糊精（DM-β-CD）时（分别为9.61和9.89）都略高些。假定五环三萜类化合物与β-CD形成1：1的包合物,对于asiaticoside-B,流动相中添加Glu-β-CD时,表观形成常数（K_F）为2534 L/mol,比添加β-CD或添加DM-β-CD时（分别为1467和1373 L/mol）都略大些。根据asiaticoside-B与β-CD包合物的红外光谱解析及计算模拟,推测asiaticoside-B的E环上甲基部分进入了β-CD的空腔内,而其羰基基团没有进入β-CD的空腔内,其糖苷部分与亲水性的β-CD空腔外部形成氢键作用力。因此,配位色谱法分离齐墩果烷型和乌苏烷型五环三萜同分异构体的分离机理可以推测如下：齐墩果烷型和乌苏烷型五环三萜同分异构体E环上甲基的不同空间位阻导致了同分异构体的不同色谱分离行为。     

MIL-101(Cr)填充针头式过滤器固相微萃取/高效液相色谱法检测水中雌激素

建立了多孔金属有机骨架MIL－101（Cr）填充针头式尼龙过滤器固相微萃取结合高效液相色谱－荧光检测器对水中雌二醇（E2）、雌三醇（E3）、雌酮（E1）3种雌激素进行快速检测的方法。MIL－101（Cr）与尼龙滤膜对雌激素表现出协同吸附效果。通过对萃取材料以及新型萃取装置制备过程、吸附、洗脱过程进行优化,可对10 mL水样中3种雌激素实现4 min吸附、1 min洗脱的快速前处理。结果显示,E2和E3在0.2～500 μg/L、E1在5～500 μg/L质量浓度范围内线性良好,相关系数（r2）为0.998 2～0.999 3,检出限分别为0.05、0.06、1.50 μg/L,日内和日间相对标准偏差（RSD）分别为0.20%～3.2%（n = 6）和 5.9%～6.1%（n = 3）。水样中3种分析物的加标回收率为84.1%～108%,RSD均不大于5.5%。该方法简单方便、灵敏度高,能够用于水样中3种雌激素的快速筛查和准确定量。     

基于铜-巯基配位聚合物电化学催化的新型乙酰胆碱酯酶电化学传感器

乙酰胆碱酯酶（AChE）是普遍存在于周围神经系统中的一种关键酶,可特异性催化底物乙酰胆碱发生水解反应,产生胆碱和醋酸盐,这一过程与阿尔兹海默症和炎症过程等相关疾病有着密切的关系.在本研究中通过硫代胆碱（TCh）与Cu（Ⅱ）反应合成了一种铜-巯基配位聚合物[命名为TCh-Cu（Ⅱ）CP],并发现该聚合物具有独特的电催化活性,基于此构建了一种用于AChE活性检测和抑制剂筛选的新型电化学生物传感平台.结果表明,该聚合物修饰在电极表面后可以催化邻苯二胺产生明显的电化学信号,信号强度与AChE浓度在0.05至100 mU·mL^-1范围内具有良好的线性关系,检出限为0.03 mU·mL^-1（S/N=3）,通过该方法还实现了AChE抑制剂的筛选.和传统的检测方法相比,该传感方法具有制备简单、选择性高和灵敏度高等特点.     

Tau蛋白的翻译后修饰与阿尔茨海默病

阿尔茨海默病（Alzheimer disease,AD）是一种常见的神经退行性疾病,由过度磷酸化Tau蛋白聚集形成的神经纤维缠结是该病主要的病理特征之一,Tau蛋白的异常磷酸化与Tau蛋白的聚集及AD的进程相关.越来越多的证据表明,Tau蛋白的异常聚集与Tau蛋白相关神经退行性疾病的发生和发展及Tau蛋白的其他翻译后修饰有一定的关系,如糖基化、乙酰化、截断、肽脯氨酸异构化、泛素化等.本文重点综述Tau蛋白翻译后修饰与AD相互关系的研究进展.     

Apolipoprotein E Recognizes Alzheimer's Disease Associated 3-O Sulfation of Heparan Sulfate

Apolipoprotein E (ApoE)’s ϵ4 alle is the most important genetic risk factor for late onset Alzheimer's Disease (AD). Cell-surface heparan sulfate (HS) is a cofactor for ApoE/LRP1 interaction and the prion-like spread of tau pathology between cells. 3-O-sulfo (3-O-S) modification of HS has been linked to AD through its interaction with tau, and enhanced levels of 3-O-sulfated HS and 3-O-sulfotransferases in the AD brain. In this study, we characterized ApoE/HS interactions in wildtype ApoE3, AD-linked ApoE4, and AD-protective ApoE2 and ApoE3-Christchurch. Glycan microarray and SPR assays revealed that all ApoE isoforms recognized 3-O-S. NMR titration localized ApoE/3-O-S binding to the vicinity of the canonical HS binding motif. In cells, the knockout of HS3ST1-a major 3-O sulfotransferase-reduced cell surface binding and uptake of ApoE. 3-O-S is thus recognized by both tau and ApoE, suggesting that the interplay between 3-O-sulfated HS, tau and ApoE isoforms may modulate AD risk.     

Experimental and computational modeling of the biological activity of benzaldehyde sulphur trioxide as a potential drug for the treatment of Alzheimer disease

Alzheimer's disease is a major public brain infection that has resulted in many deaths as revealed by the world health organization (WHO). Conventional Alzheimer treatments such as chemotherapy, surgery, and radiotherapy are not very effective and are usually associated with several adverse effects. Therefore, it is necessary to find new therapeutic approach that completely treat Alzheimer disease without much side effects. In this research work, we report the experimental and in silico molecular modeling of the biological activity of a novel azo-based compound as potential candidate for Alzheimer's disease. The synthesized compound was obtained by coupling reactions with 4-amino-3-nitrobenzaldehyde. Suitable purification and characterization techniques were employed and density functional theory (DFT) computational approach as well as in-silico molecular modeling has been employed to assess the electronic properties and anti-Alzheimer's potency. Suitable protein targets often regarded as target sites for most therapeutic vaccines for the said disease (4EY7, 1QTN, 4EY7, and 6EUE) have been selected for molecular docking investigation. For proper valuation of the drug candidacy, molecular docking studies were compared with conventional Alzheimer drug (donepezil). Also, the spectroscopic properties of the studied compound were investigated and compared with experimental data. Our findings show that the studied structure is relatively stable and expresses greater binding affinities of ?6.10, ?9.01, ?5.90, and ?11.20 kcal/mol than donepezil which had binding affinities of: 5.30, ?6.30, 5.90, and ?10.70 kcal/mol for each protein target. Thus, demonstrating the efficacy of the studied compound as potential candidate for Alzheimer's disease.     

Ginkgo biloba extract (GbE) enhances the anti-atherogenic effect of cilostazol by inhibiting ROS generation

In this study, the synergistic effect of 6-[4-(1-cyclohexyl- 1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2(1H )-quinolinone (cilostazol) and Ginkgo biloba extract (GbE) was examined in apolipoprotein E (ApoE) null mice. Co-treatment with GbE and cilostazol synergistically decreased reactive oxygen species (ROS) production in ApoE null mice fed a high-fat diet. Co-treatment resulted in a significantly decreased atherosclerotic lesion area compared to untreated ApoE mice. The inflammatory cytokines and adhesion molecules such as monocyte chemoattractant-1 (MCP-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and VCAM-1 which can initiate atherosclerosis were significantly reduced by the co-treatment of cilostazol with GbE. Further, the infiltration of macrophages into the intima was decreased by co-treatment. These results suggest that co-treatment of GbE with cilostazol has a more potent anti-atherosclerotic effect than treatment with cilostazol alone in hyperlipidemic ApoE null mice and could be a valuable therapeutic strategy for the treatment of atherosclerosis.     

Electrophoretic Determination of Formaldehyde in Human Urine: Application to Alzheimer’s Disease

The primary clinical diagnosis of Alzheimer’s disease is mainly based on medical history and neuropsychiatric inventory. It is urgent to seek biological indicators with better sensitivity and higher specificity to clinically diagnose and evaluate Alzheimer’s disease. In this work, an electrophoretic method based on 2-thiobarbituric acid derivatization and amperometric detection was developed to determine formaldehyde as a urinary biomarker of Alzheimer’s disease. Under the optimum conditions, the formaldehyde derivative was well separated from the coexisting interferences in urine sample. The limit of detection for formaldehyde was 80.0?nM (2.4?ng/?mL) based on an electrophoretic stacking technology. The average recovery values were in the range of 91.7–110%, and the relative standard deviation values were less than 4.1%. This method has been applied to analyze human urine samples from healthy volunteers and patients with different degrees of Alzheimer’s disease. The assay results showed that the content of urinary formaldehyde in patients suffering Alzheimer’s disease was significantly higher than that in healthy subjects (P?相似文献   

An ellipsometry-based Alzheimer plaque mimic: Effect of beta-amyloid, lipoprotein identity and apolipoprotein E isoform

Ca2+-induced deposition of low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), and high-density lipoprotein (HDL) at proteoheparan sulfate-modified surfaces was investigated as a function of beta-amyloid (Abeta) presence and apolipoprotein E isoform. Presence of beta-amyloid resulted in an increased deposition, as did the E4/E4 isoform compared to the corresponding E3/E3 isoform. The results are compatible with findings reported in literature on plaque formation in Alzheimer's disease, and suggest that, although simplistic, the present model system may have some potential in biosensor studies of Alzheimer plaque formation.     

Cyclic Peptides as Inhibitors of Amyloid Fibrillation

Many neurodegenerative diseases, like Parkinson’s, Alzheimer’s, or Huntington’s disease, occur as a result of amyloid protein fibril formation and cell death induced by this process. Cyclic peptides (CPs) and their derivatives form a new class of powerful inhibitors that prevent amyloid fibrillation and decrease the cytotoxicity of aggregates. The strategies for designing CPs are described, with respect to their amino acid sequence and/or conformational similarity to amyloid fibrils. The implications of CPs for the study and possible treatment of amyloid‐related diseases are discussed.     

New Cyclodextrin‐Bearing 8‐Hydroxyquinoline Ligands as Multifunctional Molecules

Recent investigations have rekindled interest in 8‐hydroxyquinolines as therapeutic agents for cancer, Alzheimer’s disease, and other neurodegenerative disorders. Three new β‐cyclodextrin conjugates of 8‐hydroxyquinolines and their copper(II) and zinc(II) complexes have been synthesized and characterized spectroscopically. In addition to improving aqueous solubility, due to the presence of the cyclodextrin moiety, the hybrid systems have interesting characteristics including antioxidant activity, and their copper(II) complexes are efficient superoxide dismutase (SOD) mimics. The ligands and their copper(II) complexes show low cytotoxicity, attributed to the presence of the cyclodextrin moiety. These compounds have potential as therapeutic agents in diseases related both to metal dyshomeostasis and oxidative stress.     

A β-sheet-targeted theranostic agent for diagnosing and preventing aggregation of pathogenic peptides in Alzheimer's disease

Amyloid-β peptide(Aβ) aggregates, particularly Aβ oligomers, are established biomarker and toxic species in Alzheimer's disease(AD). Early detection and disaggregation of Aβ aggregates are of great importance for the treatment of AD due to the unavailability of therapy at the advanced stages of the disease. A multitalented agent, 2-{2-[(1 H-benzoimidazol-2-yl)methoxy]phenyl}benzothiazole(BPB), is designed by merging two β-sheet targeting groups into one molecule to detect and inhibit the Aβaggregation. BPB can quantitatively measure the β-sheet level of soluble Aβ oligomers and specifically distinguish the aggregates of Aβ40 and Aβ42 by unique luminescence spectrum. Animal tests demonstrate that BPB can efficiently penetrate the blood brain barrier and precisely stain Aβ plaques in the brain; more importantly, it can differentiate the blood of APP transgenic mice from that of normal ones. In addition to the diagnostic potential, BPB also suppresses the generation of ROS, protects the neurons from neurotoxicity, and disaggregates the Aβ aggregates in brain homogenates of APP transgenic mice induced by metal ions or self-assembly. In view of its detective ability toward Aβ oligomers and inhibition to Aβ-related neurotoxicity, BPB may be developed into a sensitive probe for screening blood samples in the early diagnosis of AD as well as an effective inhibitor for diminishing Aβ aggregates in the treatment of the disease.     

Metabolomic approach to Alzheimer’s disease diagnosis based on mass spectrometry

Alzheimer??s disease is the most common neurodegenerative disease, but there is still no cure and early diagnosis remains very difficult. For this reason, the discovery of new biomarkers is of great importance. The application of metabolomics is emerging in this field, based on the use of mass spectrometry as a technique of analysis. In this work, blood serum samples (from Alzheimer??s disease patients and healthy controls) were analysed by mass spectrometry in order to search for potential metabolomic biomarkers. The application of multivariate statistical tools (PLS-DA) enabled us to discriminate between groups. In addition, some phosphatidylcholine compounds were identified as markers of the disease.