| 年龄相关的LRRK2 G2019S突变调控伏隔核小胶质细胞极化促进多巴胺能纤维修剪 |
| 投稿时间：2025-08-21 修订日期：2025-09-14 点此下载全文 |
| 引用本文：张秋阳,林仁河,陈朋,程云帆.年龄相关的LRRK2 G2019S突变调控伏隔核小胶质细胞极化促进多巴胺能纤维修剪[J].医学研究杂志,2026,55(1):70-76 |
| DOI：
10.11969/j.issn.1673-548X.2026.01.013 |
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| 基金项目:福建省自然科学基金资助项目(2023J011519)；福建省福州市科技计划项目(2022-S-018) |
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| 中文摘要:目的 研究年龄相关的富亮氨酸重复激酶2(leucine-rich repeat kinase 2,LRRK2)G2019S突变小胶质细胞M1/M2极化是否参与调控小胶质细胞多巴胺能纤维修剪。方法 将年轻及中年帕金森病(Parkinson′s disease,PD)模型小鼠及同窝生野生型(wild type,WT)小鼠各12只分为4组,即2月龄对照组(2M WT)、2月龄Lrrk2-G2019S组(2M GS)、10月龄对照组(10M WT)、10月龄Lrrk2-G2019S组(10M GS),每组各6只。通过免疫组织化学染色评估小胶质细胞形态、巨噬细胞抗原(cluster of differentiation 68,CD68)蛋白的表达、酪氨酸羟化酶(tyrosine hydroxylase,TH)和多巴胺转运体(dopamine transporter,DAT)密度。采用实时荧光定量聚合酶链反应法检测白细胞介素-1α(interleukin -1α,IL-1α)、肿瘤坏死因子α(tumor necrosis factor α,TNF-α)、精氨酸酶1(arginase 1,Arg1)、嗜酸性粒细胞趋化因子(chitinase-3-like protein 3,Ym1)与转化生长因子-β(transforming growth factor-beta,TGF-β)mRNA表达。Image J分析小胶质细胞吞噬DAT及TH的数量。结果 与同月龄WT小鼠及2月龄Lrrk2-G2019S突变小鼠比较,10月龄Lrrk2-G2019S突变小鼠的小胶质细胞分支数量显著减少,CD68蛋白与IL-1α mRNA表达显著上调,而Ym1与TGF-β mRNA表达显著下调,TH和DAT密度降低,小胶质细胞吞噬TH+和DAT的数量增加(P＜0.05)。结论LRRK2 G2019S突变在衰老过程可诱导小胶质细胞发生年龄依赖性形态学改变,并显著上调CD68及M1型促炎小胶质细胞标志基因的表达水平,加剧小胶质细胞的突触修剪活性,最终导致伏隔核内DAT和TH+神经元的突触结构发生异常消除。 |
| 中文关键词:LRRK2 G2019S突变 小胶质细胞 炎性细胞因子 突触修剪 |
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| Age-related LRRK2 G2019S Mutation Regulates Microglial Polarization in the Nucleus Accumbens to Promote Dopaminergic Fiber Pruning. |
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| Abstract:ObjectiveTo investigate whether M1/M2 polarization of age-related leucine-rich repeat kinase 2 (LRRK2) G2019S-mutant microglia is involved in regulating the refinement of dopaminergic fibers in microglia. Methods A total of 12 utilized young and middle-aged Parkinson′s disease (PD) model mice, along with littermate wild-type (WT) mice were divided into four groups:2-month-old control group (2M WT), 2-month-old Lrrk2-G2019S group (2M GS), 10-month-old control group (10M WT), and 10-month-old Lrrk2-G2019S group (10M GS), with six mice in each group. Immunohistochemical staining was used to evaluate microglial morphology, the expression of cluster of differentiation 68 (CD68) protein, and the density of tyrosine hydroxylase (TH) and dopamine transporter (DAT). Real-time fluorescent quantitative polymerase chain reaction was used to detect the mRNA expressions of interleukin-1α (IL-1α), tumor necrosis factor α (TNF-α), arginase-1 (Arg1), chitinase-3-like protein 3 (Ym1), and transforming growth factor-beta (TGF-β). Image J software was applied to analyze the number of DAT and TH phagocytosed by microglia. Results Compared with WT mice of the same age and 2-month-old Lrrk2-G2019S mutant mice, the 10-month-old Lrrk2-G2019S mutant mice exhibited a significant reduction in the number of microglial branches, significantly up-regulated expression of CD68 protein and IL-1α mRNA, significantly down-regulated expression of Ym1 and TGF-β mRNA, decreased density of TH and DAT, and an increased number of TH+ and DAT molecules phagocytosed by microglia (P<0.05). Conclusion During the aging process, the LRRK2 G2019S mutation can induce age-dependent morphological changes in microglia, significantly upregulate the expression levels of CD68 and M1-type pro-inflammatory microglial marker genes, exacerbate the synaptic pruning activity of microglia, and ultimately lead to the abnormal elimination of synaptic structures in DAT and TH+ positive neurons within the nucleus accumbens. |
| keywords:LRRK2 G2019S mutation Microglia Inflammatory factor Synaptic pruning |
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