Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Department of Neurology and Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Acta Neuropathol Commun. 2020 Aug 27;8(1):149. doi: 10.1186/s40478-020-01019-z.
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.
阿尔茨海默病（AD）的神经病理学变化的特征是淀粉样斑块和神经原纤维缠结（NFTs），分别由聚集的淀粉样β（Abeta）和过度磷酸化的tau 蛋白（p-tau）组成。尽管数十年来一直在研究 Abeta 和 p-tau 之间的全球关系，但在人类大脑中是否存在 Abeta 和 p-tau 之间的区域相关性仍不清楚。最近在脑脊液（CSF）中的研究表明，tau 在特定部位的磷酸化，如 T217 的磷酸化，在淀粉样斑块可检测到时的 AD 早期阶段就发生了改变。我们应用生物化学和质谱方法，在有和没有 Abeta 斑块病理学的人类大脑样本中，测量可溶性和不溶性 tau 中特定部位的磷酸化占有率。我们的定量结果确定了 AD 中多个特异性高度磷酸化的残基，包括大脑可溶性 tau 中的 T111、T153、S184（或 S185）、T205、S208、T217、S262 和 S285 位点。相比之下，大脑不溶性 tau 中最丰富的磷酸化残基是 T111、S113、T153、T181、S199、S202、T205、T217、T231、S262 和 S396。不溶性tau 中 tau 磷酸化占有率在大脑区域之间相对稳定，这表明 tau 一旦聚集成 NFT，就具有一致的磷酸化模式。我们没有发现 Abeta42 与不溶性 tau 之间的区域关联。然而，AD 大脑中可溶性 tau 的磷酸化谱与之前研究中分析的 AD CSF 中的磷酸化谱高度相关。我们还发现，大脑中 Abeta42 总量与可溶性 tau 在 T111、T153 和 T217 残基上的磷酸化占有率之间存在更高的区域相关性。这项研究深入了解了人类大脑中淀粉样变性和特定 tau 磷酸化残基之间的区域相互作用，并可能解释了在 AD CSF 中观察到的 tau 物种磷酸化特异性增加的原因。
