Tau

摘要： Dementia,for which there is no cure or effective treatment,is the leading cause of disability and death worldwide.Due to the high global prevalence and economic impact on families,caregivers,and communities,this condition represents one of the most significant public health challenges of our time.Dementia is an umbrella term describing a range of progressive neurodegenerative diseases,including Alzheimer’s disease(AD),which is the most common cause of cognitive and functional impairment among older adults.The presence of misfolded protein aggregates characterizes neurodegenerative disorders(e.g.,amyloid-beta(Aβ)and tau in AD).

摘要： Tau is an important protein of the central nervous system formed by 352-441 amino acids and encoded by the MAPT(microtubule-associated protein tau)gene on chromosome 17 which generates 6 isoforms.Tau is located in axons,dendrites,nucleus,cell membrane,and synapses of neurons.The protein is also expressed to a lesser extent in astrocytes and oligodendrocytes,although its role in these cells has been little investigated.The protein is also present in the interstitial fluid and can cross into the cerebrospinal fluid(CSF)and reach the systemic circulation.

摘要： The increase in the prevalence of individuals with Alzheimer's disease(AD)combined with the lack of a cure calls for the development of novel therapies against AD(Canter et al.,2016).The key disease-defining pathological features of AD are the accumulation of extracellular amyloid-beta(Aβ)plaques(accompanied by increasing intracellular Aβ_(1-42))and higher intracellular neu rofi brilla ry tangles,comprised mostly of hyperphosphorylated tau protein/pTau(Goedert,2015;Hardy,2017).It is evident that the elderly are more predisposed to develop AD,and thus aging is considered to be the primary risk factor for AD.By extra polation,strategies that delay aging may also slow down(if not stop)AD.

摘要： Alzheimer's disease(AD)represents the most common form of dementia and is characterized by a progressive decline of cognitive functions.Complex multifactorial processes underlie AD pathophysiology,including amyloid-beta(Aβ)toxicity,tau protein hyperphosphorylation,syna ptic dysfunction,oxidative stress,and neuroinflammation(J u and Tam,2022).

摘要： Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer’s disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phenotypic changes;these events have become a significant and promising area of research. In this review, we summarize the effects of microglial polarization and crosstalk with other cells in the central nervous system in the treatment of Alzheimer’s disease. Our literature search found that phenotypic changes occur continuously in Alzheimer’s disease and that microglia exhibit extensive crosstalk with astrocytes, oligodendrocytes, neurons, and penetrated peripheral innate immune cells via specific signaling pathways and cytokines. Collectively, unlike previous efforts to modulate microglial phenotypes at a single level, targeting the phenotypes of microglia and the crosstalk with other cells in the central nervous system may be more effective in reducing inflammation in the central nervous system in Alzheimer’s disease. This would establish a theoretical basis for reducing neuronal death from central nervous system inflammation and provide an appropriate environment to promote neuronal regeneration in the treatment of Alzheimer’s disease.

摘要： Alzheimer’s disease is a neurodegenerative disease that affected over 6.5 million people in the United States in 2021,with this number expected to double in the next 40 years without any sort of treatment.Due to its heterogeneity and complexity,the etiology of Alzheimer’s disease,especially sporadic Alzheimer’s disease,remains largely unclear.Compelling evidence suggests that brain glucose hypometabolism,preceding Alzheimer’s disease hallmarks,is involved in the pathogenesis of Alzheimer’s disease.Herein,we discuss the potential causes of reduced glucose uptake and the mechanisms underlying glucose hypometabolism and Alzheimer’s disease pathology.Specifically,decreased O-Glc NAcylation levels by glucose deficiency alter mitochondrial functions and together contribute to Alzheimer’s disease pathogenesis.One major problem with Alzheimer’s disease research is that the disease progresses for several years before the onset of any symptoms,suggesting the critical need for appropriate models to study the molecular changes in the early phase of Alzheimer’s disease progression.Therefore,this review also discusses current available sporadic Alzheimer’s disease models induced by metabolic abnormalities and provides novel directions for establishing a human neuronal sporadic Alzheimer’s disease model that better represents human sporadic Alzheimer’s disease as a metabolic disease.

摘要： Cognitive decline in Alzheimer’s disease correlates with the extent of tau pathology,in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus.Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-βor long-term depression,a form of synaptic weakening involved in learning and memory,share similar mechanisms.Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging.Conversely,certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau,in particular,phosphorylation at residue Ser396.Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau(hyper)phosphorylation.We first summarize experimental evidence regarding tau-long-term depression interactions,followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer’s disease.Finally,we conclude with some thoughts and perspectives on future research about these interactions.

摘要： Selective vulnerability of excitatory neurons in Alzheimer’s disease(AD):AD is the most common form of dementia;however,the pathogenesis of AD is largely unknown.One of the characteristic features of AD is the formation of intracellular neurofibrillary tangles(NFTs).NFTs are abnormal accumulates of misfolded tau protein,which may eventually cause neuronal death and neurodegeneration(Jack et al.,2018).In the early stages of AD progression,not all neurons are equally vulnerable to tau aggregates.Previous studies have shown that large pyramidal neurons in the entorhinal cortex(EC)are specifically vulnerable to pathological tau accumulation(Fu et al.,2017).This selective vulnerability of excitatory neurons to tau pathology is one of the fundamental questions needed to be answered in AD research.

摘要： Extracellular aggregation of amyloid-beta(Aβ)and intracellular tau tangles are two major pathogenic hallmarks and critical factors of Alzheimer’s disease.A linear interaction between Aβand tau protein has been characterized in several models.Aβinduces tau hyperphosphorylation through a complex mechanism;however,the master regulators involved in this linear process are still unclear.In our study with Drosophila melanogaster,we found that Aβregulated tau hyperphosphorylation and toxicity by activating c-Jun N-terminal kinase.Importantly,Aβtoxicity was dependent on tau hyperphosphorylation,and flies with hypophosphorylated tau were insulated against Aβ-induced toxicity.Strikingly,tau accumulation reciprocally interfered with Aβdegradation and correlated with the reduction in mRNA expression of genes encoding Aβ-degrading enzymes,including dNep1,dNep3,dMmp2,dNep4,and dIDE.Our results indicate that Aβand tau protein work synergistically to further accelerate Alzheimer’s disease progression and may be considered as a combined target for future development of Alzheimer’s disease therapeutics.

摘要： 目的探讨埃博霉素D治疗大鼠视神经损伤(TON)的治疗效果。方法42只健康SD大鼠分成埃博霉素D治疗组(1.0 mg/kg埃博霉素D腹腔注射)和等量DMSO溶剂对照组,3 d/次给药治疗直至28 d,首次给药次日建立大鼠TON模型。在3、7、28 d时运用活体闪光视觉诱发电位(FVEP)检测,免疫荧光检测,Western blot检测对两组大鼠视觉通路特性,视网膜神经节细胞(RGC)数量,受损轴突再生标志物蛋白GAP43表达水平,以及视网膜和视神经Tau及其pTau-396/404的变化情况进行研究。结果治疗组相对于对照组在3 d和28 d两个检测时间点中RGC的丢失率都显著下降(3 d下降19.12%,P=0.032;28 d下降22.67%,P=0.042),然而FVEP未能在治疗终点28 d时在生理上观测到视觉通路的改善(N2波潜伏期相对差异,P=0.236;P2-N2波振幅相对衰减差异,P=0.441)。视网膜中3 d时治疗组相对于对照组总Tau含显著增加(P<0.001),且总Tau和pTau-396/404的含量变化较一致;而在视神经轴突中,7 d时治疗组相对于对照组总Tau水平显著降低(P=0.002),但总Tau和pTau-396/404的变化关系不明显。此外,埃博霉素D的作用可使受损轴突在28 d时仍然表达GAP43。结论埃博霉素D对外伤性视神经损伤存在保护作用,其可促进损伤RGC的存活,增强存活RGC中胞体Tau的含量,降低受损轴突中Tau的累积,刺激受损轴突持续再生。

摘要： 克雅氏病(creutzfeldt－Jakob disease，CJD)是一种由朊病毒引起的致死性快速进行性神经退行性疾病，到目前为止，确诊需进行脑组织活检或尸检。脑脊液(CSF)与大脑细胞外空间接触最为紧密，因此大脑的生化改变可能会在CSF中反映出来，而CJD的病理改变主要在大脑，CSF'是显而易见的诊断标志物来源。一些研究表明在散发型CJD(sCJD)，遗传型CJD(fCJD)和新型变异型CJD(vCJD)CSF中tau蛋白浓度均升高，然而应用CFS中tau诊断CJD的敏感性和特异性还需进一步研究。本实验的目的是：为了研究CSF中tau蛋白在诊断sCJD上的敏感性和特异性，以及是否亚洲sCJD病人与其他种族病人一样CSF中tau 蛋白也同样升高。方法：本试验共检测了202份CSF样品中14-3-3和总tau蛋白含量，其中40份来自临床诊断sCJD病人，27份来自疑似sCJD病人，135份来自非CJD病人。通过Western Blot定性检测CSF中14-3-3蛋白;采用INNOGENETIC公司的ELISA kit检测CSF中总tau蛋白含量;所有病人的PRNP基因均送测序，确定129位多态性，以排除fCJD。并探讨了病人年龄、CSF取样时间、脑电图(EEG)和病人临床症状与CSF中总tau蛋白含量的相关性。结果：与疑似sCJD病人和对照相比，CSF中14－3－3蛋白的阳性率和tau蛋白浓度在临床诊断sCJD病人(P<0.001)中显著升高。用于诊断临床诊断sCJD病人时，CSF中tau蛋白浓度以大于1400 pg/mL为临界值，其特异性为94％，敏感性为90％。联合应用14-3-3和tau蛋白后特异性升高而敏感性稍有下降。统计结果表明tau蛋白浓度升高与其它主要l临床症状如年龄、性别、临床表现和采样时间都无相关性，而tau浓度与14-3－3阳性具有极高的相关性。结论：在中国临床诊断sCJD病人CSF中tau蛋白浓度显著升高，检测CSF中tau蛋白浓度可能有助于sCJD的早期诊断。

摘要： 目的:观察Alzheimer病患老脑tau、β-tubulin的表达、分布与神经元结构改变的关系.方法:采用免疫组织化学方法观察tau、β-tubulin在9例AD,5例ND脑海马、嗅球、脑室周及皮质等问位的表达并进行半定量分析.结果:(1)AD组tau蛋白与ND组相比表达明显增加(P<0.001),主要在额叶、颞叶、海马、脑室周及嗅球的表达增高(P<0.05),顶叶、枕叶无明显差异.大脑新皮层、海马神经元树突、胞体均有表达,细胞核膜部分着色,部分神经元呈典型NFT样结构;星型胶质细胞也有表达.此外,神经毡细丝、老年斑亦有广泛表达.(2)β-tubulin在ND组,主要是海马及皮质神经元树突上广泛表达,白质区少量的轴索结构也有阳表达.AD组的β-tubulin明显减少(P<0.001),额叶、颞叶、顶叶、海马及脑室周表达明显下降(P<0.05),而枕叶与嗅球无差异.(3)AD组tau与β-tubulin的阳性度之间无明显相关性(P<0.05).结论:AD患者脑内tau表达增高且有区域分布差异;β-tubulin表达减少提示AD脑内正常神经细胞骨架结构的破坏.tau与β-tubulin无明显相关性与多种因素如晚期改变、样本数少有关,尚待进一步研究.

摘要： 提供含有天然物作为有效成分的Tau蛋白产生促进剂、起因于缺乏Tau蛋白的疾病的治疗药/预防药。蚯蚓的干燥粉末、磨碎物和/或萃取物作为有效成分的Tau蛋白产生促进剂、起因于缺乏Tau蛋白的疾病的治疗药/预防药。前述起因于缺乏Tau蛋白的疾病优选为阿尔兹海默病。

摘要： 本发明属于试剂盒技术领域，尤其涉及一种Tau蛋白(TAU)检测试剂盒及其制备方法。本发明的Tau蛋白(Tau)磁微粒化学发光检测试剂盒采用长臂生物素N‑羟基琥珀酰亚胺生物素与八聚体链霉亲和素结合方式，灵敏度得到大幅提升，而且可有效避免样本中内源性生物素对检测结果的干扰，还可有效提高抗体的使用率，降低成本；本发明中使用八聚体链霉亲和素较常规的四聚体链霉亲和素拥有更多的高亲和力位点，可以结合更多的生物素连接物，配合N‑羟基琥珀酰亚胺生物素可以降低空间位阻，对灵敏度提升。

摘要： 本发明涉及基于抗体的分子(包括单结构域抗体片段、scFv分子、抗体、抗体片段、双抗体和其表位‑结合结构域)，其能够免疫特异性和选择性结合至Tau的截短的Asp421表位。这类基于抗体的分子可用于检测生物样品中的病理Tau蛋白质构象异构体(如果存在)，特别是与阿尔茨海默病或其他tau疾病的诊断和/或治疗结合，从而提供对阿尔茨海默病和其他Tau病理的诊断。本发明基于抗体的分子尤其可用作阿尔茨海默病和相关Tau疾病的诊断标记物并且用作用于治疗这类病况的药物组合物。

摘要： 本发明涉及基于抗体的分子(包括单结构域抗体片段、scFv分子、抗体、抗体片段、双抗体和其表位‑结合结构域)，其能够免疫特异性和选择性结合Tau的{p}Ser404表位。这类基于抗体的分子可用于检测生物样品中的病理Tau蛋白质构象异构体(如果存在)，特别是与阿尔茨海默病或其他tau疾病的诊断和/或治疗结合，从而提供对阿尔茨海默病和其他Tau病理的诊断。本发明基于抗体的分子尤其可用作阿尔茨海默病和相关Tau疾病的诊断标记物并且用作用于治疗这类病况的药物组合物。

摘要： 本发明涉及基于抗体的探针(包括单结构域抗体片段、scFv分子、抗体、抗体片段、双抗体和其表位结合结构域)，其能够免疫特异性且选择性结合至Tau的包含磷酸‑丝氨酸的表位，比如，例如Tau‑磷酸‑丝氨酸396/404肽。这样的显像配体可用于检测病理Tau蛋白构象异构体(如果存在于生物样品中)，特别是与阿尔茨海默病或其他tau蛋白病的诊断结合，从而提供对阿尔茨海默病和其他Tau病理的诊断。本发明的scFv分子具有作为用于阿尔茨海默病和相关tau蛋白病的诊断标记物的用途以及作为用于这些病况的治疗的药物组合物的用途。

摘要： 本公开涉及降低患有阿尔茨海默病(AD)的人或动物受试者的靶细胞中tau(τ)蛋白和/或磷酸化tau(τ)蛋白浓度的方法。本公开扩展至用于治疗阿尔茨海默病(AD)的生物药剂的用途，该生物药剂包括(i).37kDa/67kDa层粘连蛋白受体前体/高亲和力层粘连蛋白受体(LRP/LR)和/或其片段，或者(ii).用于表达LRP/LR的转染剂。

摘要： 本发明涉及使用特异性结合新Tau物种，尤其是从第11位甲硫氨酸残基开始的Tau物种的抗体治疗tau蛋白病的方法，所述甲硫氨酸被N‑α乙酰化(AcMet11‑Tau)。本发明还涉及特异性结合该新tau物种的抗体。发明人发现AcMet11‑Tau是参与Tau病理发展的病理性Tau物种。发明人通过显示AcMet11‑Tau物种的脑表达增强Thy‑Tau转基因小鼠中Tau病理的发展，并且至少通过加速Tau病理参与了病理过程，证实了AcMet11‑Tau物种与Tau病理之间的因果关系。发明人还使用基于特定单克隆抗体(2H2D11)的被动免疫方法，以证实Tau病理的Thy‑Tau22转基因模型中该Tau物种的减少/中和导致对Tau病理和相关记忆缺陷的保护作用。此外，发明人亚克隆了2C12杂交瘤并选择了2C1C8，其是另一种针对N‑α‑乙酰基‑Met11‑Tau(AcMett11‑Tau)的抗体。他们证实2C1C8抗体还显示出对Tau蛋白的N‑α末端乙酰化甲硫氨酸11的特异性，并标记了在Thy‑Tau22转基因小鼠海马体中显示神经原纤维变性的神经元。

摘要： 一种tau蛋白特异的纳米分子伴侣的制备方法及其在抑制tau聚集中的应用。首先分别合成VQIVYK‑PEG‑b‑PCL/PCL‑b‑PAE，后以VQIVYK‑PEG‑b‑PCL/PCL‑b‑PAE组装形成的复合胶束，形成tau特异的纳米分子伴侣，称为Tau‑nChap。Tau‑nChap配备了类似天然分子伴侣的疏水微域和封闭空间，可以选择性地捕获病理性tau而不是正常tau，并通过tau识别肽和表面封闭的疏水微域的协同作用有效地抑制它们的聚集。本发明有如下的优势：原料简单易得；合成步骤简单且收率高，易批量生产；聚合物胶束稳定，生物毒性低，有良好的抑制tau蛋白聚集的效果，易于推广应用。

摘要： 本发明公开了一种tau截断体蛋白在诱导tau病理聚集中的应用，首先构建了包括全长及11种tau截断体，其中tau151‑391猎获AD O‑tau的能力最强，因而将其在真核细胞中表达，提取蛋白超速离心处理后作为seeds来诱导tau的病理聚集。深入研究AD的发病机制以及针对以tau蛋白为靶标的AD治疗，获得有效的seeds尤为重要，由于获取AD患者死后的脑组织十分困难，无法提取脑组织中的AD O‑tau，因而寻找便捷有效的seeds替代AD O‑tau有重大意义。本发明不仅可以帮助我们构建AD模型，深入研究AD的发病机制、tau蛋白的传播特点，还可以为以tau为靶标的治疗提供AD模型动物。

摘要： 本公开内容提供用于治疗和诊断tau蛋白病的方法和组合物。更具体地，本公开内容涉及tau上表位的鉴定及其作为疫苗或作为试剂来产生可用于tau相关疾病的诊断和治疗二者的单克隆抗体的用途。