Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer's disease
Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer's disease
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DOI：
10.1007/s00401-018-1948-2
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发表时间：
2019-02-01
影响因子：
12.7
通讯作者：
Hoglund, Kina
中科院分区：
文献类型：
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作者：
Cicognola, Claudia;Brinkmalm, Gunnar;Hoglund, Kina
Tau是一种轴突微管结合蛋白。脑组织中的tau病理和脑脊液中tau浓度升高是阿尔茨海默病(AD)的特征。脑脊液中的tau主要以碎片形式存在。我们从脑脊液中免疫沉淀了tau，并用高分辨质谱仪鉴定了几个以氨基酸(AA)123或224结尾的内源肽。我们提出了针对分别在AA 123和224终止的tau片段的新表位特异性抗体。利用这些抗体，我们对脑组织进行了免疫组织化学，并设计了检测N-123、N-224和x-224 tau的免疫分析方法。对经病理证实的受试者(81例AD患者，33例正常对照)的可溶脑部分，3个横断面和2个纵向队列(共133例AD，38例MCI，20例MCI-AD，31例PSP，15例CBS患者和91例对照)的脑脊液，以及4例AD患者和4名对照的血清中神经和外周来源的细胞外小泡(分别为NDEV和PDEV)进行了免疫分析。抗tau224抗体染色神经原纤维缠结和神经纤维束，而抗tau123抗体仅在AD组显示较弱的胞浆染色。AD患者脑组织中N-224 tau的含量低于对照组，而N-123 tau的含量与对照组相似。在所有脑脊液队列中，AD患者的N-224 tau水平均高于对照组(p
Tau is an axonal microtubule-binding protein. Tau pathology in brain and increased tau concentration in the cerebrospinal fluid (CSF) are hallmarks of Alzheimer's disease (AD). Most of tau in CSF is present as fragments. We immunoprecipitated tau from CSF and identified several endogenous peptides ending at amino acid (aa) 123 or 224 using high-resolution mass spectrometry. We raised neo-epitope-specific antibodies against tau fragments specifically ending at aa 123 and 224, respectively. With these antibodies, we performed immunohistochemistry on brain tissue and designed immunoassays measuring N-123, N-224, and x-224 tau. Immunoassays were applied to soluble brain fractions from pathologically confirmed subjects (81 AD patients, 33 controls), CSF from three cross-sectional and two longitudinal cohorts (a total of 133 AD, 38 MCI, 20 MCI-AD, 31 PSP, 15 CBS patients, and 91 controls), and neuronally- and peripherally-derived extracellular vesicles (NDEVs and PDEVs, respectively) in serum from four AD patients and four controls. Anti-tau 224 antibody stained neurofibrillary tangles and neuropil threads, while anti-tau 123 only showed weak cytoplasmic staining in AD. N-224 tau was lower in the AD soluble brain fraction compared to controls, while N-123 tau showed similar levels. N-224 tau was higher in AD compared to controls in all CSF cohorts (p