Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
School of applied chemistry and engineering, University of Science and Technology of China, Hefei 230026, China.
Int J Mol Sci. 2019 Jan 23;20(3):487. doi: 10.3390/ijms20030487.
Alzheimer's disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been completely elucidated. It is mainly related to β-amyloid protein deposition, the hyperphosphorylation of tau protein, and the loss of neurons. The main function of tau is to assemble tubulin into stable microtubules. Under pathological conditions, tau is hyperphosphorylated, which is the major component of neurofibrillary tangles (NFT) in AD. There is considerable evidence showing that the dyshomeostasis of Zn is closely related to the development of AD. Herein, by using the third repeat unit of the microtubule-binding domain of tau (tau-R3), we investigated the effect of Zn on the aggregation and neurotoxicity of tau. Experimental results showed that tau-R3 probably bound Zn via its Cys residue with moderate affinity (association constant (Ka) = 6.82 ± 0.29 × 10⁴ M). Zn accelerated tau-R3 aggregation and promoted tau-R3 to form short fibrils and oligomers. Compared with tau-R3, Zn-tau-R3 aggregates were more toxic to Neuro-2A (N2A) cells and induced N2A cells to produce higher levels of reactive oxygen species (ROS). The dendrites and axons of Zn-tau-R3-treated neurons became fewer and shorter, resulting in a large number of neuronal deaths. In addition, both tau-R3 and Zn-tau-R3 aggregates were found to be taken up by N2A cells, and more Zn-tau-R3 entered the cells compared with tau-R3. Our data demonstrated that Zn can aggravate tau-R3 aggregation and neurotoxicity, providing clues to understand the relationship between Zn dyshomeostasis and the etiology of Alzheimer's disease.
阿尔茨海默病（AD）是一种发病率高的神经退行性疾病，受到广泛关注。然而，其发病机制尚未完全阐明。它主要与β-淀粉样蛋白沉积、tau 蛋白过度磷酸化和神经元丧失有关。tau 的主要功能是将微管蛋白组装成稳定的微管。在病理条件下，tau 过度磷酸化，是 AD 中神经原纤维缠结（NFT）的主要成分。有相当多的证据表明，Zn 的动态平衡与 AD 的发展密切相关。在此，我们使用 tau 的微管结合域的第三个重复单元（tau-R3），研究了 Zn 对 tau 聚集和神经毒性的影响。实验结果表明，tau-R3 可能通过其半胱氨酸残基与 Zn 适度结合（结合常数（Ka）= 6.82 ± 0.29×10⁴ M）。Zn 加速了 tau-R3 的聚集，并促进了 tau-R3 形成短纤维和寡聚物。与 tau-R3 相比，Zn-tau-R3 聚集体对 Neuro-2A（N2A）细胞的毒性更大，并诱导 N2A 细胞产生更高水平的活性氧（ROS）。Zn-tau-R3 处理的神经元的树突和轴突变少变短，导致大量神经元死亡。此外，tau-R3 和 Zn-tau-R3 聚集体都被 N2A 细胞摄取，并且与 tau-R3 相比，更多的 Zn-tau-R3 进入细胞。我们的数据表明，Zn 可以加重 tau-R3 的聚集和神经毒性，为理解 Zn 动态平衡与阿尔茨海默病发病机制之间的关系提供了线索。
