Gut inflammation triggers C/EBPβ/δ-secretase-dependent gut-to-brain propagation of Aβ and Tau fibrils in Alzheimer's disease
Gut inflammation triggers C/EBPβ/δ-secretase-dependent gut-to-brain propagation of Aβ and Tau fibrils in Alzheimer's disease
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DOI：
10.15252/embj.2020106320
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发表时间：
2021-07-14
期刊：
影响因子：
11.4
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
Chen, Chun;Zhou, Yunzhe;Ye, Keqiang
炎症在阿尔茨海默病（AD）的发病机制中起着重要作用。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未完全了解。以年龄依赖的方式在3xTg AD小鼠模型中研究了结肠中的C/EBPβ/δ - 分泌酶信号传导。我们对3xTg小鼠长期施用1%葡聚糖硫酸钠（DSS）以引发肠道渗漏，或者向结肠注射Aβ或Tau纤维或AD患者脑裂解物，并结合切除/切断肠 - 脑连接的迷走神经（迷走神经切断术），以探索肠 - 脑轴在AD样病理发展中的作用，并监测在这些条件下的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，引发Aβ和Tau纤维形成并扩散到大脑。DSS处理以C/EBPβ/δ - 分泌酶依赖的方式促进肠道渗漏，并促进3xTg小鼠肠道和大脑中的AD样病理。迷走神经切断术选择性地减弱这种信号传导，减轻Aβ和Tau病理，并恢复学习和记忆。注射到结肠中的Aβ或Tau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，这些病理随后通过迷走神经传递到大脑。
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/EBP beta/delta-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 A beta 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/EBP beta/delta-secretase signaling under those conditions. We found that C/EBP beta/delta-secretase signaling is temporally activated in the gut of AD patients and 3xTg mice, initiating formation of A beta 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/EBP beta/delta-secretase-dependent manner. Vagotomy selectively blunts this signaling, attenuates A beta and Tau pathologies, and restores learning and memory. A beta 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/EBP beta/delta-secretase and initiates AD-associated pathologies in the gut, which are subsequently transmitted to the brain via the vagus nerve.