Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Alzheimers Dis. 2021;81(4):1403-1418. doi: 10.3233/JAD-210297.
Recent studies show that an increased T217-phosphorylation of tau in plasma could diagnose AD at an early stage with high accuracy and high specificity, while the potential toxic role of tau T217-phosphorylation is not known.
To study the potential toxic role of tau T217-phosphorylation.
We performed stereotactic brain injection, behavioral testing, immunohistochemistry and immunofluorescence, western blotting, Golgi staining, in vitro recombinant tau polymerization, and other measurements.
We first constructed tau T217-wild-type (T217), T217-phospho-mimic (T217E), and T217-non-phospho-mimic (T217A) plasmids or their virus vectors on the basis of wild-type tau. We found that expressing tau-T217E induced a significantly increased tau phosphorylation at multiple AD-associated sites with inhibited proteolysis and increased cleavage/fibrillization of tau, while expressing tau-T217A abolished the above changes of tau both in vitro and in vivo. By mutating T217E on tau-P301L, a dominant mutation identified in patients with frontotemporal dementia, we did not observe significant exacerbation of tau-P301L phosphorylation and cognitive impairment although the increased tau cleavage and propagation were shown.
T217-phosphorylation exacerbates wild-type tau hyperphosphorylation with aggravated tau cleavage/fibrillization and cognitive impairments, while overexpressing T217E on the basis P301L does not exacerbate tau phosphorylation or the P301L-induced cognitive deficits, although it aggravates tau cleavage and propagation.
最近的研究表明，血浆中 tau 的 T217 磷酸化增加可以以高准确性和特异性诊断 AD，而 tau T217 磷酸化的潜在毒性作用尚不清楚。
研究 tau T217 磷酸化的潜在毒性作用。
我们进行了立体定向脑内注射、行为测试、免疫组织化学和免疫荧光、western blot、Golgi 染色、体外重组 tau 聚合等测量。
我们首先在野生型 tau 的基础上构建了 tau T217-野生型（T217）、T217-磷酸模拟型（T217E）和 T217-非磷酸模拟型（T217A）质粒或其病毒载体。我们发现，表达 tau-T217E 可诱导 tau 在多个 AD 相关位点的磷酸化显著增加，同时伴有蛋白水解抑制和 tau 的裂解/纤维化增加，而表达 tau-T217A 可在体外和体内均消除 tau 的上述变化。通过在 tau-P301L 上突变 T217E，tau-P301L 是额颞叶痴呆患者中发现的一个显性突变，尽管显示 tau 裂解和传播增加，但我们没有观察到 tau-P301L 磷酸化和认知障碍的显著恶化。
T217 磷酸化加剧了野生型 tau 的过度磷酸化，加重了 tau 的裂解/纤维化和认知障碍，而在 P301L 的基础上过度表达 T217E 不会加剧 tau 磷酸化或 P301L 引起的认知缺陷，尽管它会加剧 tau 的裂解和传播。
