钙调磷酸酶对阿尔茨海默病中tau蛋白异常磷酸化的作用

100年前,阿尔茨海默病（Alzheimer disease,AD）被首次报道,它是一种以进行性认知障碍和记忆力损伤为主要临床特征的中枢神经系统退行性疾病,是最常见的一种老年性痴呆.由异常磷酸化的tau蛋白构成的神经元纤维缠结（neurofibrillary tangle,NFT）是AD最重要的病理学改变之一.钙调磷酸酶（calcineurin,CN）是脑组织中含量最高的一种丝氨酸/苏氨酸蛋白磷酸酶,其活性依赖于Ca2＋和钙调蛋白.最近的研究显示,CN在脑中与NFT共定位,CN活性的下降能够导致tau蛋白在多个AD特征性位点的异常磷酸化,进而形成NFT.因而,CN活性的缺陷与AD的发生密切相关.CN活性缺陷导致的tau蛋白异常磷酸化具有可逆性,CN激活剂有望在其中扮演重要的角色.     

阿尔茨海默病中Tau蛋白与线粒体损伤

阿尔茨海默病(Alzheimer’s disease, AD)是一种神经退行性疾病,过度磷酸化tau异常聚集形成的神经纤维缠结是其主要病理特征之一。线粒体损伤在AD发病机制中发挥重要作用,是AD的早期病理事件,而其又与tau蛋白密切相关。文中总结了AD中病理性tau蛋白对线粒体动力学、形态、自噬、功能等方面造成的损伤,并展望了从保护线粒体损伤角度研发防治AD药物的可行性。     

氧化应激与阿尔茨海默病

阿尔茨海默病(Alzheimer disease,AD)是一种多病因神经退行性疾病,以β-淀粉样蛋白(Aβ)聚集沉积引起的老年斑(senile plaque,SP),聚集的磷酸化微管稳定蛋白质(tau)引起的细胞内神经原纤维缠结(neurofibrillary tangle,NFT)为主要病理特征。活性氧(ROS)和活性氮(RNS)的增加引起的氧化应激和抗氧化防御酶功能丧失在AD形成中具有重要作用。综述近年来这方面的研究进展,着重总结了AD中的生物大分子(脂质、蛋白质和核酸)氧化以及Aβ和金属离子(铁、铜和锌等)动态平衡紊乱诱导的氧化应激与AD的关系,同时介绍了AD中氧化应激相关的信号转导,旨在对今后这方面的研究及预防和治疗AD提供帮助。     

建立超敏ELISA-双酶底物循环法检测tau蛋白

利用酶联免疫吸附法(ELISA)的高特异性和双酶底物循环的高灵敏度,建立了ELISA-双酶底物循环扩增检测法.用传统ELISA测定纯化tau蛋白和阿尔茨海默病异常磷酸化tau蛋白的范围值分别为1～32 ng和0.2～10 ng,而此法的测定范围值分别为0.75～200 pg和0.5～50 pg,比传统ELISA的灵敏度分别提高1 300倍和400倍,可测定范围值亦分别扩大了8.5倍和2倍.可准确测定阿尔茨海默病患者脑脊液样品中的微量tau蛋白和异常磷酸化tau蛋白,为阿尔茨海默病的早期诊断和鉴别诊断提供了新技术.     

脑脊液β-淀粉样蛋白/磷酸化tau蛋白比值在鉴别诊断阿尔茨海默病与血管性痴呆中的价值

目的:探讨脑脊液Aβ1-42、t-tau蛋白及p-tau181蛋白以及Aβ1-42/t-tau和Aβ1-12/p-tau181比值鉴别诊断阿尔茨海默病(AD)与血管性痴呆(VD)的临床应用价值.方法:采用酶联免疫吸附法检测AD患者、VD患者和正常对照组(NC)脑脊液中Aβ1-42、t-tau蛋白及P-tau181蛋白浓度的变化.结果:An组患者脑脊液Aβ1-42越浓度显著低于VD组和NC组,t-tan蛋白及p-tau181蛋白浓度显著高于VD组和NC组.当Aβ1-42/p-tau181比值分界值为11.3时,鉴别诊断AD与VD的敏感性和特异性分别为95%和94%.结论:脑脊液Aβ1-42、t-tau蛋白及p-tau181蛋白浓度的变化,尤其是Aβ1-42/p-tau181比值是很好的AD与VD鉴别诊断的生物学指标.     

tau蛋白异常翻译后修饰在阿尔茨海默病中的作用

在阿尔茨海默病（A1zheimer’s disease,AD）中微管相关蛋白tau能够产生许多异常翻译后修饰并聚集形成配对螺旋丝（paired helical filament,PHF）。这些tau的修饰包括过磷酸化、异常糖基化、截断等,其中,过磷酸化和异常糖基化是阿尔茨海默氏病等神经退行性疾病神经元纤维化的主要分子发病机制。     

载脂蛋白E与阿尔茨海默病的关系

阿尔茨海默病(Alzheimer disease,AD)是最常见的一种老年性痴呆症,临床上以进行性记忆丧失和认知功能障碍为特征。流行病学资料表明,载脂蛋白E(apolipoprotein E,ApoE)的基因多态性与AD密切相关。ApoE不但影响了AD的发生年龄与危险性,还与AD特征性病理改变神经原纤维缠结(neurofibrillary tangle,NFT)和老年斑(senile plaque,SP)共定位。研究发现,ApoE可促进β-淀粉样肽(β—amyloid peptide,Aβ)的沉积和SP的形成,C末端切除的ApoE片段则促使Tau蛋白的过度磷酸化及NFT的形成,并进一步引起神经变性和行为缺陷。同时,ApoE还与炎症因子的表达相关。上述证据均提示了ApoE及其基因多态性在AD发病机制中的重要作用。     

蛋白激酶A与阿尔茨海默病

阿尔茨海默病 (Ａｌｚｈｅｉｍｅｒｄｉｓｅａｓｅ ,ＡＤ)是老年痴呆症中最常见的一种 ,主要表现为进行性的记忆和认知功能障碍。目前ＡＤ的病因和发病机制尚不明了。神经原纤维缠结(ｎｅｕｒｏｆｉｂｒｉｌｌａｒｙｔａｎｇｌｅ ,ＮＦＴ)作为ＡＤ的特征性病变 ,与临床痴呆症状呈正相关 ,提示ＮＦＴ在ＡＤ的发病过程中可能发挥重要作用[1] 。ＮＦＴ以成对螺旋丝样结构 (ｐａｉｒｅｄｈｅｌｉｃａｌｆｉｌａ ｍｅｎｔ,ＰＨＦ)存在 ,其主要成分是异常过度磷酸化的ｔａｕ蛋白 (ｔａｕｐｒｏｔｅｉｎ) [2 ] 。Ｔａｕ蛋白在成人脑中有 6种同分异…     

针对tau蛋白PET 示踪剂研究进展

阿尔茨海默病(Alzheimer's disease,AD)是一种常见的中枢神经系统退行性疾病,脑内主要病理变化为神经元外由β-淀粉样蛋白(Amyloidβ,Aβ)沉积形成的老年斑(Senile Plaques,SP)和神经元内由异常过度磷酸化的微管相关tau蛋白构成的神经原纤维缠结(Neurofibrillary Tangles,NFTs),对这两种病理改变的特异性识别有助于AD早期发现与诊断。既往针对AD的PET示踪剂多数作用于Aβ,近年tau蛋白类PET示踪剂发展迅速,以[18F]THK-523、[18F]THK-5105和[18F]THK-5117为代表的tau蛋白靶向PET示踪剂在AD的诊断与治疗方面显示出巨大的发展潜力与应用前景。     

阿尔茨海默病(Alzheimer’s Disease,AD)与动力相关蛋白1(dynamin-related protein 1,Drp1)

阿尔茨海默病(AD)已成为威胁老年人生活的一种常见病,对老年人的生活质量有着严重的影响,目前尚无有效地防治方法。最新研究发现在阿尔茨海默病的病理发生中,神经细胞伴有显著的线粒体代谢紊乱和动态变化的异常,其中动力相关蛋白1(Drp1)是参与线粒体动态变化的关键分子。深入研究阿尔茨海默病中线粒体动态变化的异常及Drp1等关键分子的作用机制,对于揭示AD的发生机制及寻找药物作用靶点具有重要意义。综述了Drp1在阿尔茨海默病中的调控机制。     

Tau Aggregation in Alzheimer's Disease

The crucial role of the neuronal Tau protein in microtubule stabilization and axonal transport suggests that too little or too much Tau might lead to neuronal dysfunction. The presence of a hyper-phosphorylated but non-aggregated molecule as a toxic species that might sequester normal Tau is discussed. We present recent in vitro results that might allow to dissect the role of individual phosphorylation sites on its structure and function. We also discuss in this review the role of phosphorylation for the aggregation of the neuronal Tau protein, and compare it to the aggregation induced by external poly-anions.     

Tau蛋白在阿尔茨海默病中的作用

阿尔茨海默病(AD)是非常普遍的神经变性性疾病并且是老年人痴呆的主要原因。AD患者的症状特点包括进行性的认知障碍、记忆丧失和行为障碍,与大脑中的病理变化密切相关。AD现成为全球最严重的健康和社会经济问题。在AD患者脑中神经纤维网或神经营养障碍的过程中存在tau蛋白的异常。tau蛋白丧失其促微管组装的生物学功能,导致细胞骨架的破坏、丝状物形成和神经缠结,轴突运输损害,进而导致突触蛋白失去功能和神经退行性病变。其数量和结构的改变将会影响其功能而且会出现异常聚集。调节Tau蛋白的异常聚集的分子机制主要是一些翻译后修饰使其结构及构象发生变化。因此,异常磷酸化和截断的tau蛋白作为tau蛋白病理过程的关键机制而引起学者关注。本文描述了tau蛋白的结构和功能及其在AD中的主要病理变化,同时在本文中还涉及到磷酸化的tau蛋白是神经元对氧化应激的代偿反应这一观点。对tau蛋白进行更加全面的解读。     

Tau蛋白在阿尔兹海默病治疗中的研究进展

阿尔兹海默病中一个重要的病理特点是神经原纤维缠结(NFTs),其与Tau蛋白具有密切的关系。Tau蛋白是含量最高的微管相关蛋白。正常Tau蛋白可与微管蛋白结合促进其有效聚合形成微管。而过度磷酸化的Tau蛋白则会自我聚集,进而导致NFTs的形成。近年来,国内外就Tau为主要靶点治疗AD有了很大进展。本文就Tau蛋白在AD中的病理学意义,与Aβ蛋白的相互作用以及以Tau为主要切入点对AD进行治疗的方法作一综述。     

Tau PET Imaging for Staging of Alzheimer's Disease in Down Syndrome

Alzheimer's disease (AD) pathology and early‐onset dementia develop almost universally in Down syndrome (DS). AD is defined neuropathologically by the presence of extracellular plaques of aggregated amyloid β protein and intracellular neurofibrillary tangles (NFTs) of aggregated hyperphosphorylated tau protein. The development of radiolabeled positron emission tomography (PET) ligands for amyloid plaques and tau tangles enables the longitudinal assessment of the spatial pattern of their accumulation in relation to symptomatology. Recent work indicates that amyloid pathology develops 15–20 years before neurodegeneration and symptom onset in the sporadic and autosomal dominant forms of AD, while tau pathology correlates more closely with symptomatic stages evidenced by cognitive decline and dementia. Recent work on AD biomarkers in DS illustrates similarities between DS and sporadic AD. It may soon be possible to apply recently developed staging classifications to DS to obtain a more nuanced understanding of the development AD in DS and to provide more accurate diagnosis and prognosis in the clinic.     

Thermodynamics of the Interaction between Alzheimer's Disease Related Tau Protein and DNA

Tau hyperphosphorylation can be considered as one of the hallmarks of Alzheimer''s disease and other tauophaties. Besides its well-known role as a microtubule associated protein, Tau displays a key function as a protector of genomic integrity in stress situations. Phosphorylation has been proven to regulate multiple processes including nuclear translocation of Tau. In this contribution, we are addressing the physicochemical nature of DNA-Tau interaction including the plausible influence of phosphorylation. By means of surface plasmon resonance (SPR) we measured the equilibrium constant and the free energy, enthalpy and entropy changes associated to the Tau-DNA complex formation. Our results show that unphosphorylated Tau binding to DNA is reversible. This fact is in agreement with the protective role attributed to nuclear Tau, which stops binding to DNA once the insult is over. According to our thermodynamic data, oscillations in the concentration of dephosphorylated Tau available to DNA must be the variable determining the extent of Tau binding and DNA protection. In addition, thermodynamics of the interaction suggest that hydrophobicity must represent an important contribution to the stability of the Tau-DNA complex. SPR results together with those from Tau expression in HEK cells show that phosphorylation induces changes in Tau protein which prevent it from binding to DNA. The phosphorylation-dependent regulation of DNA binding is analogous to the Tau-microtubules binding inhibition induced by phosphorylation. Our results suggest that hydrophobicity may control Tau location and DNA interaction and that impairment of this Tau-DNA interaction, due to Tau hyperphosphorylation, could contribute to Alzheimer''s pathogenesis.     

Experimental Diabetes Mellitus Exacerbates Tau Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Diabetes mellitus (DM) is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. There is increasing evidence that insulin also plays a role in Alzheimer''s disease (AD) as it is involved in the metabolism of β-amyloid (Aβ) and tau, two proteins that form Aβ plaques and neurofibrillary tangles (NFTs), respectively, the hallmark lesions in AD. Here, we examined the effects of experimental DM on a pre-existing tau pathology in the pR5 transgenic mouse strain that is characterized by NFTs. pR5 mice express P301L mutant human tau that is associated with dementia. Experimental DM was induced by administration of streptozotocin (STZ), which causes insulin deficiency. We determined phosphorylation of tau, using immunohistochemistry and Western blotting. Solubility of tau was determined upon extraction with sarkosyl and formic acid, and Gallyas silver staining was employed to reveal NFTs. Insulin depletion by STZ administration in six months-old non-transgenic mice causes increased tau phosphorylation, without its deposition or NFT formation. In contrast, in pR5 mice this results in massive deposition of hyperphosphorylated, insoluble tau. Furthermore, they develop a pronounced tau-histopathology, including NFTs at this early age, while the pathology in sham-treated pR5 mice is moderate. Whereas experimental DM did not result in deposition of hyperphosphorylated tau in non-transgenic mice, a predisposition to develop a tau pathology in young pR5 mice was both sufficient and necessary to exacerbate tau deposition and NFT formation. Hence, DM can accelerate onset and increase severity of disease in individuals with a predisposition to developing tau pathology.     

Tau 蛋白磷酸化在阿尔茨海默病中所处的地位

阿尔茨海默病(Alzheimer’s disease,AD)是一种老年人常见的神经系统退行性疾病,是痴呆最常见的病因。AD患者越来越多,给家属及社会带来严重负担造成了巨大的家庭和社会负担,这就迫使我们进一步探讨AD发病机制。在AD的众多发病机制中,tau蛋白假说倍受青睐。在蛋白磷酸酯酶2A(protein phosphatase 2A,PP2A)、糖原合酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)、细胞周期依赖性蛋白激酶-5(cyclin-dependent kinase 5,CDK-5)和Bcl-2等蛋白酶及调节蛋白作用下,微管相关蛋白tau蛋白以其异常磷酸化结构或是形成二聚体、寡聚体和神经原纤维缠结等形式,参与到AD的病理过程。Tau蛋白及其相关结构,可能启动或促进了AD的凋亡,亦可能抑制了急性凋亡却促进了慢性的神经细胞变性。揭开这一谜底,可能揭开AD病理改变的神秘面纱。