Research Article- Role of Fe(II)/(III), Cu(II), and Zn(II) in Alzheimer's Disease Pathogenesis-The case for a metal-mediated tau aggregation

Tau protein aggregation and its hyperphosphorylation play an important role in the pathogenesis of Alzheimer's disease. There is also considerable evidence for the accumulation of Fe(II)/(III), Cu(II), and Zn(II) in the brain of Alzheimer's patients, although their involvement in the etiology of the disease remains unknown. Here, interactions of the 3d metal ions Fe(II)/(III), Cu(II), and Zn(II) with the longest isoform of the human tau protein (htau40) are studied in detail. Electrospray mass spectrometry and ion mobility mass spectrometry analyses confirm the interactions of metal species with tau and that these interactions cause structural changes. Phosphorylation of the full-length htau40 with glycogen synthase kinase 3β (GSK3β), a protein kinase, causes a reduction in metal interactions. Transmission electron microscopy studies of the tau aggregates formed in the presence of metal ions suggest that the presence of metal ions influences the aggregation process. Fluorescence studies of full-length htau40 in the presence of Cu(II) indicate the formation of reactive oxygen species, which may contribute further to oxidative stress and neuronal death. References: (1) Ahmadi, S.; Zhu, S.; Sharma, R.; Wu, B.; Soong, R.; Majumdar, R. D.; Wilson, D. J.; Simpson, A. J.; Kraatz, H.-B. Aggregation of Microtubule Binding Repeats of Tau Protein Is Promoted by Cu2+. ACS Omega 2019, 4 (3), 5356–5366. https://doi.org/10.1021/acsomega.8b03595. (2) Ahmadi, S.; Wu, B.; Song, R.; Zhu, S.; Simpson, A.; Wilson, D. J.; Kraatz, H. B. Exploring the Interactions of Iron and Zinc with the Microtubule Binding Repeats R1 and R4. J. Inorg. Biochem. 2020, 205, 110987. https://doi.org/10.1016/j.jinorgbio.2019.110987. (3) Ahmadi, S.; Ebralidze, I. I.; She, Z.; Kraatz, H.-B. Electrochemical Studies of Tau Protein-Iron Interactions—Potential Implications for Alzheimer’s Disease. Electrochim. Acta 2017, 236, 384–393. https://doi.org/10.1016/j.electacta.2017.03.175.

Tau蛋白聚集及其过度磷酸化在阿尔茨海默病（Alzheimer's disease）的发病机制中发挥重要作用。诸多研究证实，阿尔茨海默病患者脑内存在Fe(II)/(III)、Cu(II)与Zn(II)的蓄积，尽管这些金属离子在该病病因学中的具体作用仍未明确。本研究针对3d过渡金属离子Fe(II)/(III)、Cu(II)及Zn(II)与人类tau蛋白最长同工型（htau40）的相互作用展开了系统且详细的探究。电喷雾质谱（electrospray mass spectrometry）与离子迁移质谱（ion mobility mass spectrometry）分析结果证实，金属物种可与tau蛋白特异性结合，且该结合过程会诱导蛋白结构发生改变。利用蛋白激酶糖原合酶激酶3β（glycogen synthase kinase 3β, GSK3β）对全长htau40进行磷酸化修饰，可显著降低其与金属离子的结合亲和力。对金属离子存在条件下形成的tau聚集体开展透射电子显微镜（transmission electron microscopy）表征，结果显示金属离子的存在会对tau蛋白的聚集过程产生显著影响。针对Cu(II)存在体系中全长htau40的荧光光谱分析显示，该体系会生成活性氧物种（reactive oxygen species），这可能进一步加剧氧化应激并诱导神经元死亡。
参考文献：
(1) Ahmadi, S.; Zhu, S.; Sharma, R.; Wu, B.; Soong, R.; Majumdar, R. D.; Wilson, D. J.; Simpson, A. J.; Kraatz, H.-B. Cu2+促进tau蛋白微管结合重复序列的聚集. ACS Omega 2019, 4 (3), 5356–5366. https://doi.org/10.1021/acsomega.8b03595.
(2) Ahmadi, S.; Wu, B.; Song, R.; Zhu, S.; Simpson, A.; Wilson, D. J.; Kraatz, H. B. 铁、锌与微管结合重复序列R1、R4的相互作用研究. J. Inorg. Biochem. 2020, 205, 110987. https://doi.org/10.1016/j.jinorgbio.2019.110987.
(3) Ahmadi, S.; Ebralidze, I. I.; She, Z.; Kraatz, H.-B. tau蛋白与铁相互作用的电化学研究——对阿尔茨海默病的潜在启示. Electrochim. Acta 2017, 236, 384–393. https://doi.org/10.1016/j.electacta.2017.03.175.