弓形虫TgCtwh3 Δrop16Ⅰ/Ⅲ加速急性感染小鼠神经元凋亡和APP产生

IF 2.9 Q3 NEUROSCIENCES

IBRO Neuroscience Reports Pub Date : 2025-06-01 DOI:10.1016/j.ibneur.2025.05.009

Di Yang , Cong Wang , Qing Tao , Lei Liu , Mengmeng Jin , Haiping Cai , Meijuan Zheng , Mengtao Gong , Li Yu , Jian Du , Qingli Luo , Jilong Shen , Kunpeng Qin , Deyong Chu

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引用次数: 0

摘要

目的探讨rop16Ⅰ/Ⅲ-缺陷/gra15Ⅱ-显性刚地弓形虫中国1基因型Wh3 （TgCtwh3 Δrop16Ⅰ/Ⅲ）菌株在体内外诱导神经元凋亡、APP和BACE1产生的机制。方法分别腹腔注射TgCtwh3野生型（TgCtwh3 WT）和TgCtwh3 Δrop16Ⅰ/Ⅲ速殖子感染balb /c小鼠。感染1周后，采用苏木精-伊红（H&；E）和尼氏染色法检测海马神经元形态和数量。应用western blotting和qRT-PCR检测海马组织中凋亡相关蛋白、APP、BACE1以及炎症因子蛋白和基因的表达水平。分别用TgCtwh3 WT和TgCtwh3 Δrop16Ⅰ/Ⅲ速殖子感染海马神经元细胞系HT22，通过免疫荧光染色和western blotting分析靶蛋白的表达情况。流式细胞术检测HT22细胞凋亡。结果注射TgCtwh3 Δrop16Ⅰ/Ⅲ速殖子的balb /c小鼠出现外观、姿态改变、活力下降等异常。海马实验显示TgCtwh3 Δrop16Ⅰ/Ⅲ弓形虫引起神经元丢失、神经元排列紊乱、神经元核异常、深度染色和神经元凋亡。此外，TgCtwh3 Δrop16Ⅰ/Ⅲ速殖子与感染TgCtwh3 WT速殖子的小鼠相比，在海马组织中产生了明显的APP、bace1和促炎因子的表达增加。相反，TgCtwh3 Δrop16Ⅰ/Ⅲ感染小鼠的关键抗炎细胞因子转化生长因子β1 （TGF-β1）的表达显著降低。进一步研究发现TgCtwh3 Δrop16Ⅰ/Ⅲ速速子通过触发ERS诱导HT22细胞凋亡，同时通过激活NF-κB信号通路促进HT22产生APP、BACE1。结论GRA15Ⅱ效应因子可能在神经元凋亡、促炎因子分泌、APP、BACE1生成等过程中发挥重要作用。相反，ROP16Ⅰ/Ⅲ效应物可能在这一过程中发挥潜在的保护作用。

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Toxoplasma TgCtwh3 Δrop16Ⅰ/Ⅲ accelerates neuronal apoptosis and APP production in mouse with acute infection

Objective

To explore the mechanism by which rop16_Ⅰ/Ⅲ-deficient/gra15_Ⅱ-dominant toxoplasma gondii Chinese 1 genotype Wh3 (TgCtwh3 Δrop16_Ⅰ/Ⅲ) strain induced neuron apoptosis, APP and BACE1 production in vivo and vitro.

Method

BALB/c mice were infected by intraperitoneal injection with TgCtwh3 wild type (TgCtwh3 WT) and TgCtwh3 Δrop16_Ⅰ/Ⅲ tachyzoites, respectively. One week after infection, the morphology and number of hippocampal neurons were examined by hematoxylin-eosin (H&E) and Nissl staining. Expression levels of apoptosis-related proteins, APP, BACE1 as well as inflammatory factors proteins and genes in the hippocampus were evaluated using western blotting and qRT-PCR. The hippocampal neuron cell line HT22 was infected with TgCtwh3 WT and TgCtwh3 Δrop16_Ⅰ/Ⅲ tachyzoite, respectively, and the expression of target proteins was analyzed through immunofluorescence staining and western blotting. Furthermore, HT22 apoptosis was assessed using flow cytometry.

Result

BALB/c mice injected with TgCtwh3 Δrop16_Ⅰ/Ⅲ tachyzoites presented abnormal appearance and posture changes as well as declined vitality. The hippocampus assay demonstrated that TgCtwh3 Δrop16_Ⅰ/Ⅲ toxoplasma caused neuron loss, neuron alignment disorder, neuronal nucleus abnormal deep-stained and neuron apoptosis. Furthermore, TgCtwh3 Δrop16_Ⅰ/Ⅲ tachyzoites caused obvious production of APP, BACE1and expression increase of pro-inflammatory factors in hippocampal tissue compared to these in mice infected with TgCtwh3 WT tachyzoites. Contrarily, the expression of transforming growth factor beta 1 (TGF-β1), a pivotal anti-inflammatory cytokine was significantly decreased in TgCtwh3 Δrop16_Ⅰ/Ⅲ infected mice. Further study showed that TgCtwh3 Δrop16_Ⅰ/Ⅲ tachyzoites induced HT22 apoptosis through triggering ERS, meanwhile promoted HT22 to produce APP, BACE1 by activating NF-κB signaling pathway.

Conclusion

Our results indicated that the GRA15_Ⅱ effector may play a crucial part in neuron apoptosis, pro-inflammatory factors secretion, and APP, BACE1 production. Inversely, ROP16_Ⅰ/Ⅲ effector may play a potentially protective role in this process.

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