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Gut inflammation triggers C/EBPβ/δ-secretase-dependent gut-to-brain propagation of Aβ and Tau fibrils in Alzheimer’s disease
The EMBO Journal ( IF 11.4 ) Pub Date : 2021-07-14 , DOI: 10.15252/embj.2020106320
Chun Chen 1 , Yunzhe Zhou 2 , Hualong Wang 1, 3 , Ashfaqul Alam 4 , Seong Su Kang 1 , Eun Hee Ahn 1 , Xia Liu 1 , Jianping Jia 2 , Keqiang Ye 1
Affiliation  

Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Some evidence suggests that misfolded protein aggregates found in AD brains may have originated from the gut, but the mechanism underlying this phenomenon is not fully understood. C/EBPβ/δ-secretase signaling in the colon was investigated in a 3xTg AD mouse model in an age-dependent manner. We applied chronic administration of 1% dextran sodium sulfate (DSS) to trigger gut leakage or colonic injection of Aβ or Tau fibrils or AD patient brain lysates in 3xTg mice and combined it with excision/cutting of the gut–brain connecting vagus nerve (vagotomy), in order to explore the role of the gut–brain axis in the development of AD-like pathologies and to monitor C/EBPβ/δ-secretase signaling under those conditions. We found that C/EBPβ/δ-secretase signaling is temporally activated in the gut of AD patients and 3xTg mice, initiating formation of Aβ and Tau fibrils that spread to the brain. DSS treatment promotes gut leakage and facilitates AD-like pathologies in both the gut and the brain of 3xTg mice in a C/EBPβ/δ-secretase-dependent manner. Vagotomy selectively blunts this signaling, attenuates Aβ and Tau pathologies, and restores learning and memory. Aβ or Tau fibrils or AD patient brain lysates injected into the colon propagate from the gut into the brain via the vagus nerve, triggering AD pathology and cognitive dysfunction. The results indicate that inflammation activates C/EBPβ/δ-secretase and initiates AD-associated pathologies in the gut, which are subsequently transmitted to the brain via the vagus nerve.

中文翻译:

肠道炎症触发阿尔茨海默病中 Aβ 和 Tau 原纤维的 C/EBPβ/δ-分泌酶依赖性肠到脑传播

炎症在阿尔茨海默病 (AD) 的发病机制中起重要作用。一些证据表明,在 AD 大脑中发现的错误折叠的蛋白质聚集体可能起源于肠道,但这种现象背后的机制尚不完全清楚。在 3xTg AD 小鼠模型中以年龄依赖性方式研究了结肠中的 C/EBPβ/δ-分泌酶信号传导。我们在 3xTg 小鼠中长期施用 1% 葡聚糖硫酸钠 (DSS) 来触发肠道渗漏或结肠注射 Aβ 或 Tau 原纤维或 AD 患者脑裂解物,并将其与肠-脑连接迷走神经 (迷走神经切断术) 的切除/切断相结合),以探索肠-脑轴在 AD 样病理发展中的作用,并在这些条件下监测 C/EBPβ/δ-分泌酶信号传导。我们发现 C/EBPβ/δ-分泌酶信号在 AD 患者和 3xTg 小鼠的肠道中被暂时激活,开始形成扩散到大脑的 Aβ 和 Tau 原纤维。DSS 治疗以 C/EBPβ/δ-分泌酶依赖性方式促进肠道渗漏并促进 3xTg 小鼠肠道和大脑中的 AD 样病变。迷走神经切断术选择性地减弱这种信号传导,减弱 Aβ 和 Tau 病变,并恢复学习和记忆。注入结肠的 Aβ 或 Tau 原纤维或 AD 患者脑裂解物通过迷走神经从肠道传播到大脑,引发 AD 病理和认知功能障碍。结果表明,炎症激活 C/EBPβ/δ-分泌酶并在肠道中引发与 AD 相关的病理,随后通过迷走神经传递到大脑。
更新日期:2021-09-01
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