以微管相关蛋白Tau为靶点的抗阿尔茨海默病药物研究进展

阿尔茨海默病(AD)是老年人最常见的神经退行性疾病。微管相关蛋白tau 的改变与AD发病和进展密切相关。以tau 蛋白为靶标进行AD防治药物研究已成为近年AD研究领域的一大热点,主要包括抑制tau 蛋白磷酸化、聚集,加速tau 蛋白解聚。本文对以tau蛋白为靶标的AD防治药物研究的现状进行综述。     

钙蛋白酶参与tau蛋白过度磷酸化和截断的机制研究进展

阿尔茨海默病(AD)是最常见的神经退行性疾病之一,临床表现为认知和记忆功能障碍。钙蛋白酶(calpain)在细胞中广泛地被激活,钙蛋白酶的紊乱会引起AD病理学中tau蛋白过度磷酸化和tau蛋白的异常剪切。钙蛋白酶通过影响糖原合成酶激酶3和蛋白磷酸酶2A的活性,从而使tau蛋白多个位点发生异常过度磷酸化,并且介导tau蛋白单体的截断,诱导神经变性。钙蛋白酶有望成为AD药物治疗的潜在靶点。     

脑脊液tau蛋白预测阿尔茨海默病的Meta分析

目的 评价脑脊液(CSF)总tau蛋白(t-tau)和磷酸化tau蛋白(P-tau)浓度预测阿尔茨海默病(Alzheimer'S disease,AD)的有效性和准确性.方法 全面检索tau蛋白浓度预测轻度认知功能障碍(mild cognitive impairment,MCI)转化为AD的诊断性试验文献,评价纳入文献...     

Alzheimer病早期生化诊断指标的进展

Alzheimer病 (AD)的早期诊断是其治疗和预后的限制性因素。目前从AD患者脑脊液中发现一些具有诊断意义的生化指标有tau蛋白 ,β 淀粉样蛋白 (Aβ) ,载脂蛋白E(ApoE) ,Aβ的前体蛋白 (APP) ,早老素 (PS 1 ,PS 2 )和天冬氨酸转氨酶 (AST)等。其中以脑脊液中的tau蛋白 ,尤其是过度磷酸化tau蛋白 (p tau)有可能成为AD的早期诊断的生化指标。     

Alzheimer病脑脊液诊断标志物研究新进展

Alzheimer病（AD）是发生在早老及老年期以进行性痴呆为主和精神行为异常的大脑变性疾病。近十年来AD已被列入主要危害老年人健康疾病的一种。但AD的诊断迄今为止仍是神经精神科临床的一大难题，目前仍采用排除法，确诊主要靠尸检。经多年努力，从实验方法中寻找一种无创性的生前诊断方法已初见成效，许多研究已论及脑脊液（CSF）是否含有支持AD诊断的特异性标志物，本文回顾有关研究，简介如下。1微管相关蛋白（tau－蛋白）近年研究证明，tau－蛋白异常磷酸化并转变成为双股螺旋神经纤维蛋白丝（PHF）导致了AD病人脑组织中营养不良…     

麻醉与阿尔茨海默病相关研究进展

阿尔茨海默病(AD)是一种慢性进展的神经系统退行性疾病,可造成严重的社会和经济负担。其病理改变包括细胞外β淀粉样蛋白沉积成的老年斑以及异常磷酸化的tau蛋白造成的胞内神经纤维缠结。但AD的病因和危险因素仍不清楚。现基础及临床研究一致认为麻醉暴露史与AD的疾病进程相关。本文旨在阐述AD的病理生理以及麻醉暴露史与AD的相关研究。     

Alzheimer病早期生化诊断指标的进展

Alzheimer病（AD）的早期诊断是其治疗和预后的限制性因素。目前从AD患者脑脊液中发现一些具有诊断意义的生化指标有tau蛋白,β－淀粉样蛋白（Aβ）,载脂蛋白E（ApoE),Aβ的前体蛋白（APP）,早老素（PS－1,PS－2）和天冬氨酸转氨酶（AST）等。其中以脑脊液中的tau蛋白,尤其是过度磷酸化tau蛋白（p-tan）有可能成为AD的早期诊断的生化指标。     

线粒体功能障碍在阿尔茨海默病发病中的作用

阿尔茨海默病(AD)是一种常见的老年中枢神经系统退行性疾病,其主要的组织病理学特点是神经元的大量丢失和由病理性淀粉样蛋白(amyloid-β,Aβ)集聚而形成的细胞外老年斑的沉积,以及细胞内高度磷酸化的tau蛋白所形成的神经元纤维缠结(neurofibrillary tangles,NFTs)[1]。AD既存在与年     

电针对阿尔茨海默病模型动物认知功能和组织病理学影响的研究进展

随着人口老龄化的发展,阿尔茨海默病(AD)的发病率逐渐升高。电针以百会为中心的不同穴位,能够改善AD模型动物的认知功能、脑部形态、β-淀粉样蛋白沉积以及tau蛋白磷酸化等。     

首发精神分裂症患者血清NCAM、tau蛋白、磷酸化tau蛋白水平与神经功能指标及认知功能的关系

目的 探讨首发精神分裂症患者血清神经细胞黏附分子(NCAM)、tau蛋白、磷酸化tau蛋白水平与神经功能指标及认知功能的关系.方法 选择2017年10月至2019年12月该院精神科收治的62例首发精神分裂症患者(精神分裂组)和51例健康志愿者(对照组)作为研究对象.检测血清NCAM、tau蛋白、磷酸化tau蛋白、脑源性...     

快速老化小鼠SAMP8 在阿尔茨海默病研究中的应用

阿尔茨海默病以进行性认知功能障碍、记忆能力下降为主要特征。脑内β-淀粉样蛋白(Aβ)异常沉积、神经原纤维缠结、胆碱能神经元功能减退、突触和树突棘缺失等为阿尔茨海默病特征性病理改变。快速老化小鼠SAMP8 在早期即出现学习记忆功能障碍、Aβ异常沉积、tau 蛋白磷酸化、神经递质改变、突触结构和功能障碍、生理节律紊乱,以及基因表达等多方面的特征性改变,与人类阿尔茨海默病病理改变较为一致,可以作为较理想的动物模型,用于阿尔茨海默病防治药物的研究。     

阻断酪氨酸蛋白激酶Src表达对蛋白磷酸酯酶2A活性和tau蛋白磷酸化的影响

目的:研究细胞内酪氨酸蛋白激酶Src对蛋白磷酸酯酶2A(PP2A)酪氨酸307位点(Y307)磷酸化和活性以及tau蛋白磷酸化的影响,为阿尔茨海默病脑内PP2A活性下调和tau蛋白异常磷酸化机制提供实验依据。方法:体外培养小鼠成神经瘤N2a细胞,转染特异性阻断Src表达的SiRNA,检测转染不同时间点PP2A Y307的磷酸化水平、PP2A的活性以及tau蛋白在不同位点的磷酸化水平。结果:转染Src SiRNA 12 h时Src蛋白水平显著降低,PP2A Y307的磷酸化水平下降,但总的PP2A蛋白水平也降低,伴随PP2A活性下调,tau蛋白在Ser198/199/202位点发生过度磷酸化。结论:细胞内PP2A活性的调节受多种因素的影响,单纯阻断上游Src的表达可降低PP2A的活性,并导致tau蛋白的过度磷酸化。     

The Excitotoxin Quinolinic Acid Induces Tau Phosphorylation in Human Neurons

Some of the tryptophan catabolites produced through the kynurenine pathway (KP), and more particularly the excitotoxin quinolinic acid (QA), are likely to play a role in the pathogenesis of Alzheimer's disease (AD). We have previously shown that the KP is over activated in AD brain and that QA accumulates in amyloid plaques and within dystrophic neurons. We hypothesized that QA in pathophysiological concentrations affects tau phosphorylation. Using immunohistochemistry, we found that QA is co-localized with hyperphosphorylated tau (HPT) within cortical neurons in AD brain. We then investigated in vitro the effects of QA at various pathophysiological concentrations on tau phosphorylation in primary cultures of human neurons. Using western blot, we found that QA treatment increased the phosphorylation of tau at serine 199/202, threonine 231 and serine 396/404 in a dose dependent manner. Increased accumulation of phosphorylated tau was also confirmed by immunocytochemistry. This increase in tau phosphorylation was paralleled by a substantial decrease in the total protein phosphatase activity. A substantial decrease in PP2A expression and modest decrease in PP1 expression were observed in neuronal cultures treated with QA. These data clearly demonstrate that QA can induce tau phosphorylation at residues present in the PHF in the AD brain. To induce tau phosphorylation, QA appears to act through NMDA receptor activation similar to other agonists, glutamate and NMDA. The QA effect was abrogated by the NMDA receptor antagonist memantine. Using PCR arrays, we found that QA significantly induces 10 genes in human neurons all known to be associated with AD pathology. Of these 10 genes, 6 belong to pathways involved in tau phosphorylation and 4 of them in neuroprotection. Altogether these results indicate a likely role of QA in the AD pathology through promotion of tau phosphorylation. Understanding the mechanism of the neurotoxic effects of QA is essential in developing novel therapeutic strategies for AD.     

The reinterpretation of the immunochemical study of Alzheimer neurofibrillary tangles

Many studies have been done on neurofibrillary tangles occurring in Alzheimer's disease using antibodies, but without agreement on the interpretation of the results. Immunochemical studies using antibodies to neurofilament and tau and the antibody, Alz50, were carried out to estaslish a common view. The results suggest that: 1) antibodies to neurofilament recognizing tangles react with the phosphorylated epitope of tau in paired helical filaments; 2) Alz50 reacts with abnormal tau, which has slower electrophoretic mobility than normal tau; and 3) a certain part of tau has the protease-resistant property in brains affected by the disease.     

Aluminium, amyloid, and Alzheimer's disease.

Alzheimer's disease is a degenerative disease characterized by the presence of numerous senile plaques and neurofibrillary tangles, primarily in the cortical areas of the brain. There is no known cause of the disease, although exposure to aluminium has been implicated by epidemiological studies and the finding of aluminium in the cerebral plaques and tangles. There is a genetic predisposition for early-onset disease, and Down's syndrome patients are particularly vulnerable. Many of the plaques contain amyloid, and a gene for amyloid precursor protein has been identified on the long arm of chromosome 21. It is possible that the amyloid plaques arise through over-expression of this gene. Since there is no specific marker for Alzheimer's disease, laboratory investigations are restricted to confirming the disease after the patient has died. Recent immunohistochemical studies have been directed towards showing the relationships between the neurones, senile plaques and neurofibrillary tangles, and the presence of amyloid and filament proteins such as tau, ubiquitin and neurofilaments.     

脑脊液Tau蛋白测定在老年性痴呆诊断中的意义

目的探讨阿尔茨海默病(AD)患者脑脊液Tau蛋白含量变化的临床意义。方法采用夹心酶联免疫吸附法(ELISA)测定了18例AD、16例多发性梗死性痴呆(MID)、19例其他神经系统疾病患者脑脊液中Tau蛋白含量。结果脑脊液中Tau蛋白含量,3组间差异有非常显著意义(P<0.01);AD组与MID组间及AD组与对照组间差异均有非常显著意义(分别为P<0.01和P<0.01);MID组和对照组间差异无显著意义(P>0.05)。AD组患者脑脊液中Tau蛋白含量随年龄有增高趋势,但统计学检验与年龄无相关关系(P>0.05)。轻、中、重度痴呆患者间的差异无显著性(P>0.05)。结论脑脊液Tau蛋白的升高有助于AD的诊断和鉴别诊断。     

Tau as a therapeutic target in neurodegenerative disease

Tau is a microtubule-associated protein thought to help modulate the stability of neuronal microtubules. In tauopathies, including Alzheimer's disease and several frontotemporal dementias, tau is abnormally modified and misfolded resulting in its disassociation from microtubules and the generation of pathological lesions characteristic for each disease. A recent surge in the population of people with neurodegenerative tauopathies has highlighted the immense need for disease-modifying therapies for these conditions, and new attention has focused on tau as a potential target for intervention. In the current work we summarize evidence linking tau to disease pathogenesis and review recent therapeutic approaches aimed at ameliorating tau dysfunction. The primary therapeutic tactics considered include kinase inhibitors and phosphatase activators, immunotherapies, small molecule inhibitors of protein aggregation, and microtubule-stabilizing agents. Although the evidence for tau-based treatments is encouraging, additional work is undoubtedly needed to optimize each treatment strategy for the successful development of safe and effective therapeutics.     

洛伐他汀减轻冈田酸诱导的大鼠皮质神经元Tau蛋白过度磷酸化

目的探讨洛汀(LOV)对冈田酸(OA)诱导的大鼠皮质神经元Tau蛋白过度磷酸化的影响。方法选用孕期17d的SD大鼠,取皮质神经元接种培养。待优化OA处理时间和剂量等条件后,实验分为阴性对照组、OA组、LOV组、LOV预处理+OA组。通过免疫印迹法检测皮层神经元Tau蛋白磷酸化水平、总Tau蛋白水平。结果应用OA 30 nmmol/L处理大鼠皮质神经元1 h,成功诱导Tau蛋白过度磷酸化,而不明显影响细胞活力。LOV 500 nM预处理4 d能在Thr181(AT270),Thr231(AT180),Ser202/Thr205(AT8)和Ser396等磷酸化位点显著减轻冈田酸诱导的大鼠皮质神经元Tau蛋白过度磷酸化,而不影响总Tau蛋白水平。结论洛伐他汀减轻冈田酸诱导的大鼠皮质神经元Tau蛋白过度磷酸化,提示洛伐他汀对Tau相关神经病理有潜在的神经保护作用。