Alzheimer’s disease (AD) neuropathologic change is characterized by amyloid plaques and neurofibrillary tangles (NFTs) that consist of aggregated amyloid beta (Abeta) and hyperphosphorylated tau proteins (p-tau), respectively. Although the global relationship between Abeta and p-tau has been studied for decades, it is still unclear whether a regional correlation exists between Abeta and p-tau in the human brain. Recent studies in cerebrospinal fluid (CSF) have suggested that tau phosphorylation at specific sites such as T217 is modified at an early stage of AD when amyloid plaques become detectable. We applied biochemical and mass spectrometry methods in human brain samples with and without Abeta plaque pathology to measure site-specific phosphorylation occupancies in soluble and insoluble tau. Our quantitative results identified multiple residues specifically hyper-phosphorylated in AD, including at sites T111, T153, S184 (or S185), T205, S208, T217, S262, and S285 in brain soluble tau. In contrast, the most enriched phosphorylated residues in brain insoluble tau were T111, S113, T153, T181, S199, S202, T205, T217, T231, S262, and S396. Tau phosphorylation occupancies in the insoluble fraction were relatively constant across brain regions, suggesting that tau has a consistent phosphorylation pattern once it has aggregated into NFTs. We did not find regional association between Abeta42 and insoluble tau. However, the phosphorylation profile of soluble tau in AD brain was highly correlated to that in AD CSF, which was analyzed in a previous study. We also found a higher regional association between total Abeta42 and soluble tau phosphorylation occupancy at residues T111, T153 and T217 in the brain. This study provides insights into regional interactions between amyloidosis and specific tau phosphorylated residues in the human brain and may explain the specific increases of tau species phosphorylation observed in AD CSF.

中文翻译：

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大脑中淀粉样蛋白和tau磷酸化的生化指标的区域相关性。

阿尔茨海默氏病（AD）神经病理学改变的特征是淀粉样蛋白斑块和神经原纤维缠结（NFT），分别由聚集的淀粉样蛋白β（Abeta）和超磷酸化的tau蛋白（p-tau）组成。尽管已经研究了Abeta和p-tau之间的全球关系数十年，但仍不清楚人脑中Abeta和p-tau之间是否存在区域相关性。最近对脑脊液（CSF）的研究表明，在AD的早期阶段，当淀粉样蛋白斑变得可检测时，特定位点（例如T217）的tau磷酸化被修饰。我们在有和没有Abeta斑块病理的人脑样本中应用了生化和质谱方法，以测量可溶和不可溶tau蛋白的位点特异性磷酸化占有率。我们的定量结果鉴定了AD中多个特异磷酸化的残基，包括脑可溶tau中的位点T111，T153，S184（或S185），T205，S208，T217，S262和S285。相反，脑不溶性tau中最富集的磷酸化残基为T111，S113，T153，T181，S199，S202，T205，T217，T231，S262和S396。Tau的不溶部分中的Tau磷酸化在整个大脑区域相对恒定，这表明tau聚集到NFT中后具有一致的磷酸化模式。我们没有发现Abeta42和不溶性tau之间的区域关联。但是，AD脑中可溶性tau的磷酸化曲线与AD CSF中的高度相关，这在先前的研究中已经进行了分析。我们还发现在大脑中的残基T111，T153和T217的总Abeta42和可溶性tau磷酸化占有率之间存在更高的区域关联。这项研究提供了对淀粉样变性和人脑中特定tau磷酸化残基之间区域相互作用的见解，并可以解释AD CSF中观察到的tau物种磷酸化的特定增加。