Dual Effects: Intrastriatal Injection of α-syn N103/tau N368 Preformed Fibrils Promotes Endogenous α-synuclein Aggregates in the Proximal Colon
Dual Effects: Intrastriatal Injection of α-syn N103/tau N368 Preformed Fibrils Promotes Endogenous α-synuclein Aggregates in the Proximal Colon
复制标题
双重效应：纹状体内注射 α-syn N103/tau N368 预制原纤维促进近端结肠内源性 α-突触核蛋白聚集
DOI：
10.3233/jpd-223294
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Xuebing Cao
中科院分区：
文献类型：
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作者：
Jialing Wang;Xiaoman Yang;Weiqi Zeng;Xiaoqian Zhang;Xiaomei Yang;Yu Xu;Ke Liu;Zhaoyuan Zhang;Yan Xu;Xuebing Cao
背景：脑的病理变化可以影响胃肠道，而脑肠轴的证据较少。目的：确定脑内源性磷酸化α-突触核蛋白是否通过迷走神经介导的脑-肠轴诱导胃肠道功能障碍。研究方法：将α-syn N103/tau N368预成纤维注射到啮齿类动物的背侧纹状体内，分析脑和结肠突触核蛋白病和肠神经系统的变化。此外，还进行了膈下迷走神经切断术以确认迷走神经在脑肠传播中的作用。结果如下：在1个月时观察到磷酸化α-突触核蛋白主要通过迷走神经从脑到近端结肠的顺行传播。随着时间的推移，在近端结肠中检测到磷酸化α-突触核蛋白的蓄积，并伴有粘膜和粘膜下层中巨噬细胞和嗜酸性粒细胞的浸润。在注射较低剂量的预形成的原纤维后，磷酸化α-突触核蛋白的积累和多巴胺能神经元的损失在6个月时降低至与对照一致的水平，而GFAP、Iba-1和IL-6的表达水平增加。在高预成型纤维剂量条件下，粪便性状和胃肠动力在6个月时显著降低，出现磷酸化α-突触核蛋白聚集和IL-1β水平升高。结论：诱导的内源性α-synuclein主要通过迷走神经快速进入近端结肠。注射低剂量的预制原纤维可引起肠神经系统的恢复和α-突触核蛋白聚集体的降解，而高剂量则导致病理性α-突触核蛋白的蓄积、肠道炎症和显著的胃肠道功能障碍。
Background: Pathological changes in the brain can affect the gastrointestinal tract, whereas there is less evidence regarding the brain-gut axis. Objective: To identify whether cerebral endogenous phosphorylated α-synuclein induces gastrointestinal dysfunction via the brain-gut axis, mediated by the vagus nerve. Methods: α-syn N103/tau N368 preformed fibrils were injected into the dorsal lateral striatum of rodents, and the cerebral and colonic synucleinopathies and changes in the enteric nervous system were analyzed. Moreover, subdiaphragmatic vagotomy was conducted to confirm the role of the vagus nerve in brain-gut propagation. Results: An anterograde propagation of phosphorylated α-synuclein from the brain to the proximal colon mainly via the vagus nerve was observed at one month. The accumulation of phosphorylated α-synuclein was detected in the proximal colon over time, accompanied by infiltration of macrophages and eosinophils in the mucosa and submucosa. Upon injection with lower doses of preformed fibrils, the accumulation of phosphorylated α-synuclein and dopaminergic neuron loss was reduced to levels consistent with control at six months, while the expression levels of GFAP, Iba-1, and IL-6 increased. Under high preformed fibrils dose conditions, fecal traits and gastrointestinal motility were significantly reduced at six months, and aggregations of phosphorylated α-synuclein and an increasing level of IL-1β appeared. Conclusion: Induced endogenous α-synuclein can quickly propagate into the proximal colon mainly via the vagus nerve. Injections of low doses of preformed fibrils can elicit recovery of the enteric nervous system and degradation of α-synuclein aggregates whereas high doses cause accumulation of pathological α-synuclein, enteric inflammation, and prominent gastrointestinal dysfunction.