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

Abstract

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.

Mesoporous silica nanoparticle-encapsulated Bifidobacterium attenuates brain Aβ burden and improves olfactory dysfunction of APP/PS1 mice by nasal delivery

“…Most studies on the gut–brain axis have focused on ascending signals from the intestine, with less attention on signals from the central nervous system [ 37 , 38 ]. In addition, bacteria as nanoparticle carriers can enhance tissue penetration [ 31 ].…”

pTDP-43 aggregates accumulate in the gut and other non-central nervous system tissues prior to symptom onset in amyotrophic lateral sclerosis

“…This finding of gut pathology preceding motor symptoms is also seen in Tau, Ab and alphasynuclein animal models [17,18]. In these models, it has been hypothesised that the pathology originates in the gut and progresses to involve the CNS when there was (i) a physical connection (intact vagus nerve) and (ii) systemic inflammation [17,18]. When these two conditions were not met, central neuronal pathology did not develop.…”

Differential Transcriptomic Profiles Following Stimulation with Lipopolysaccharide in Intestinal Organoids from Dogs with Inflammatory Bowel Disease and Intestinal Mast Cell Tumor

“…It has been suggested that IBD inflammation may be exacerbated by a disruption of the renin–angiotensin system [ 142 ]. Additionally, inflammation contributes significantly to the etiology of Alzheimer’s disease (AD) by activating C/EBPβ/δ-secretase and causing AD-associated disorders in the gut, which are then transferred to the brain via the vagus nerve [ 143 ]. BACE1 and BACE2 β-secretases have been widely investigated in the context of Alzheimer’s disease.…”