Gut inflammation triggers C/EBPβ/δ‐secretase‐dependent gut‐to‐brain propagation of Aβ and Tau fibrils in Alzheimer’s disease

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. SYNOPSIS Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). The misfolded protein aggregates found in AD brains have been suggested to originate in the gut in some previous studies. This study shows that inflammation can activate C/EBPβ/δ‐secretase and initiate AD pathologies in the gut, which are subsequently transported to the brain via the vagus nerve. C/EBPβ/δ‐secretase signaling is activated in the gut of AD patients and 3xTg mice in an age‐dependent manner, initiating Aβ and Tau fibril formation that propagates to the brain. Dextran sodium sulfate (DSS) triggers 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 attenuates C/EBPβ/δ‐secretase signaling, diminishes Aβ and tau pathologies and rescues the learning and memory. Colonic injected