Hippocampal Galectin-3 knockdown alleviates lipopolysaccharide-induced neurotoxicity and cognitive deficits by inhibiting TLR4/NF-?B signaling in aged mice
Hippocampal Galectin-3 knockdown alleviates lipopolysaccharide-induced neurotoxicity and cognitive deficits by inhibiting TLR4/NF-?B signaling in aged mice
复制标题
海马半乳糖凝集素 3 敲低通过抑制老年小鼠的 TLR4/NF-κB 信号传导来减轻脂多糖诱导的神经毒性和认知缺陷。
DOI：
10.1016/j.ejphar.2022.175360
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发表时间：
2022-11-12
影响因子：
5
通讯作者：
Yan, Zhiwen
中科院分区：
文献类型：
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作者：
Chen, Fang;Wu, Xiaofeng;Yan, Zhiwen
神经炎症被认为有助于阿尔茨海默病（AD）的发病和进展。半乳糖凝集素-3（Galectin-3）是半乳糖凝集素嵌合亚家族的唯一成员，是神经炎症和小胶质细胞活化的关键调节因子。然而，Gal-3抑制在AD相关神经炎症中的作用尚不清楚。在这里，我们研究了海马Gal-3敲低是否减轻脂多糖（LPS）诱导的神经毒性和认知缺陷，以及潜在的机制。首先，我们将抗Gal-3短发夹RNA双侧注射到老年小鼠（23月龄）海马齿状回，然后系统地给予LPS。为了确定海马Gal-3敲低对神经炎症反应和神经元凋亡的影响，我们评估了Gal-3沉默对LPS暴露的老年小鼠海马中促炎细胞因子、小胶质细胞活化和凋亡水平的影响。行为测试用于评估小鼠的认知功能。为了探索潜在的信号传导，对来自小鼠脑的蛋白质提取物进行分析TLR 4/NF-κ B通路的关键分子（包括Toll样受体4（TLR 4）、髓样分化因子88和核转录因子-κ B（NF-κ B）p65）的表达水平，并且在Gal-3刺激之前用TLR 4抑制剂或NF-κ B抑制剂预处理BV 2细胞。这些分析表明，海马Gal-3敲低减弱了LPS攻击的老年小鼠海马中的神经炎症和神经元凋亡，这与认知功能的改善有关。海马Gal-3基因敲低可能通过抑制TLR 4/NF-kB通路来保护LPS诱导的神经毒性。我们的研究结果突出了Gal-3作为AD相关神经炎症的潜在治疗靶点。
Neuroinflammation is thought to contribute to the onset and progression of Alzheimer's disease (AD). Galectin-3 (Gal-3), the only member of the galectin chimeric subfamily, is a key regulator of neuroinflammation and microglial activation. However, the effects of Gal-3 inhibition in AD-related neuroinflammation are unclear. Here, we investigated whether hippocampal Gal-3 knockdown alleviated lipopolysaccharide (LPS)-induced neurotoxicity and cognitive deficits, as well as the underlying mechanisms. First, we bilaterally injected aged mice (23 months old) with anti-Gal-3 short hairpin RNA into the hippocampus dentate gyrus, followed by sys-temic LPS administration. To determine the effects of hippocampal Gal-3 knockdown on neuroinflammatory response and neuronal apoptosis, we assessed the effects of Gal-3 silencing on the levels of pro-inflammatory cytokines, microglial activation, and apoptosis in the hippocampus of LPS-exposed aged mice. Behavioral tests were used to access the cognitive function of the mice. To explore the potential signaling, protein extracts from the brains of mice were subjected to analyze the expression levels of key molecules (including Toll-like receptor 4 (TLR4), myeloid differentiation factor 88, and nuclear transcription factor-kappa B (NF-kappa B) p65) of the TLR4/NF-kB pathway, and BV2 cells were pretreated with TLR4 inhibitor or NF-kappa B inhibitor before Gal-3 stimulation. These analyses showed that hippocampal Gal-3 knockdown attenuated neuroinflammation and neuronal apoptosis in the hippocampus of LPS-challenged aged mice, and this was associated with improved cognitive function. Hippocampal Gal-3 knockdown may protect against LPS-induced neurotoxicity by inhibiting the TLR4/NF-kB pathway. Our findings highlight Gal-3 as a potential therapeutic target against AD-associated neuroinflammation.