Tau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer's disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0-I, II or III-IV, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We found that soluble tau multimers are strongly increased at Braak stages III-IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs or misfolded oligomers at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau multimerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble multimers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs. These findings shed light on early PTM changes of tau during AD pathogenesis in human brains.

中文翻译：

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翻译后修饰标记定义了与早期阿尔茨海默氏病脑中的寡聚相关的可溶性tau的变化。

Tau是一种微管结合蛋白，可以接受各种翻译后修饰（PTM），包括磷酸化，甲基化，乙酰化，糖基化，硝化，磺酰化和截短。τ的过度磷酸化与其聚集和神经原纤维缠结（NFT）的形成有关，这是阿尔茨海默氏病（AD）的标志。尽管先前已在NFT tau上检测到70多个磷酸化位点，但尚缺乏AD早期人类大脑中寡聚和去污剂可溶tau的研究。在这里，我们应用了全面的电化学发光ELISA分析来分析25个不同的PTM位点以及对照和散发性AD脑中的tau寡聚。样本分为Braak阶段0-I，II或III-IV，对应于整个大脑区域的显微镜下可检测到的tau病理学进展。我们发现可溶性tau多聚体在Braak阶段III-IV期间在所有研究的脑区域中都显着增加，包括颞皮层，该皮层在此病理阶段不包含NFT或错误折叠的寡聚体。我们还确定了五个磷酸化位点，这些磷酸化位点在同一供体的整个内嗅皮层，海马和颞皮层中持续不断地增加。这些位点中的三个与所有三个脑区域中的tau多聚化相关，但不与通常用于NFT免疫组化检测的磷酸敏感抗体的表位重叠。因此，我们的结果表明可溶性多聚体的特征是与特定于成熟NFT的事件不同的一小部分特定的磷酸化事件。这些发现为人类大脑AD发病过程中tau的早期PTM变化提供了启示。