Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain
Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain
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DOI：
10.1186/s40478-020-01019-z
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发表时间：
2020-08-27
影响因子：
7.1
通讯作者：
Sato, Chihiro
中科院分区：
文献类型：
--
作者：
Horie, Kanta;Barthelemy, Nicolas R.;Sato, Chihiro
阿尔茨海默病 (AD) 神经病理变化的特征是淀粉样斑块和神经原纤维缠结 (NFT)，分别由聚集的淀粉样β (Abeta) 和过度磷酸化 tau 蛋白 (p-tau) 组成。尽管 Abeta 和 p-tau 之间的整体关系已经研究了几十年，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，当淀粉样斑块变得可检测到时，特定位点（例如 T217）的 tau 磷酸化在 AD 早期发生了改变。我们在有或没有 Abeta 斑块病理学的人脑样本中应用生化和质谱方法来测量位点特异性磷酸化占据 insolu 和 insoluso tau。我们的定量结果确定了 AD 中特异性过度磷酸化的多个残基，包括脑可溶性 tau 蛋白中的 T111、T153、S184（或 S185）、T205、S208、T217、S262 和 S285 位点。相比之下，脑不溶性 tau 蛋白中最富集的磷酸化残基是 T111、S113、T153、T181、S199、S202、T205、T217、T231、S262 和 S396。不溶性部分中的 tau 磷酸化占据在整个大脑区域相对恒定，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 和不溶性 tau 之间的区域关联。然而，AD 脑中可溶性 tau 的磷酸化谱与 AD CSF 中的磷酸化谱高度相关，这在之前的研究中进行了分析。我们还发现大脑中残基 T111、T153 和 T217 处的总 Abeta42 与可溶性 tau 磷酸化占据率之间存在较高的区域关联。这项研究提供了对淀粉样变性和人脑中特定 tau 磷酸化残基之间的区域相互作用的见解，并可能解释 AD CSF 中观察到的 tau 物种磷酸化的特定增加。
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 insolubleandinsolubletau. 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.