Zhao Jie, Chen Jie, Lu Jing, Shi Qihui, Wang Qingyi, Gao Zhonghong, Zeng Linghui, Liu Qiong
Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China.
Shenzhen Key Laboratory of Marine Bioresource and Eco-Environmental Sciences, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China.
J Neurochem. 2025 Sep;169(9):e70218. doi: 10.1111/jnc.70218.
The abnormal generation and aggregation of Aβ has been considered the central pathogenic mechanism of Alzheimer's disease (AD). Soluble Aβ tends to aggregate into toxic oligomers, which initiate neuronal dysfunction. Therefore, attenuation of Aβ oligomer formation might be an effective therapeutic strategy for AD. It has been reported that Aβ can be nitrated at tyrosine 10. Our previous study found that nitration of Y10 in Aβ significantly inhibits its aggregation and reduces its toxicity. However, the effects of Aβ nitration on its neurotoxicity remain unclear. Here, we used SH-SY5Y cells and a mouse model of AD induced by intrahippocampal Aβ oligomer injection to investigate the effects of tyrosine nitration on the neurotoxicity of Aβ. The results of dot blot, gel electrophoresis analysis, transmission electron microscopy, atomic force microscopy, and dynamic light scattering indicated that nitration of Y10 in Aβ inhibits its oligomerization. Aβ treatment perturbed the integrity of intracellular membranes, eventually leading to apoptosis of SH-SY5Y cells. In contrast, nitrated Aβ exhibited little neurotoxicity toward SH-SY5Y cells. Additionally, mice injected with Aβ oligomer developed cognitive impairment in behavioral tests. Aβ oligomer caused neurotoxicity in the hippocampus of the mice, possibly through triggering apoptosis and neuroinflammation and promoting aberrant amyloid processing. As expected, nitrated Aβ also had little effect on physiological and cognitive capacities. These results further confirm that nitration of Y10 in Aβ can significantly inhibit its neurotoxicity. Moreover, our findings contribute to the understanding of the role of Aβ in the development of AD.
Aβ的异常生成和聚集被认为是阿尔茨海默病（AD）的核心致病机制。可溶性Aβ倾向于聚集成有毒的寡聚体，从而引发神经元功能障碍。因此，减少Aβ寡聚体的形成可能是治疗AD的有效策略。据报道，Aβ在酪氨酸10位点可发生硝化。我们之前的研究发现，Aβ中Y10的硝化显著抑制其聚集并降低其毒性。然而，Aβ硝化对其神经毒性的影响仍不清楚。在此，我们使用SH-SY5Y细胞和海马内注射Aβ寡聚体诱导的AD小鼠模型来研究酪氨酸硝化对Aβ神经毒性的影响。斑点印迹、凝胶电泳分析、透射电子显微镜、原子力显微镜和动态光散射的结果表明，Aβ中Y10的硝化抑制其寡聚化。Aβ处理扰乱了细胞内膜的完整性，最终导致SH-SY5Y细胞凋亡。相比之下，硝化的Aβ对SH-SY5Y细胞几乎没有神经毒性。此外，注射Aβ寡聚体的小鼠在行为测试中出现认知障碍。Aβ寡聚体在小鼠海马中引起神经毒性，可能是通过触发细胞凋亡和神经炎症以及促进异常的淀粉样蛋白加工。正如预期的那样，硝化的Aβ对生理和认知能力也几乎没有影响。这些结果进一步证实，Aβ中Y10的硝化可显著抑制其神经毒性。此外，我们的发现有助于理解Aβ在AD发展中的作用。
