Gut dysbiosis contributes to amyloid pathology, associated with C/EBPβ/AEP signaling activation in Alzheimer's disease mouse model.

• Type of Material: Article
• Authors: Chun Chen, Emory University; Eun Hee Ahn, Emory University; Seong Kang, Emory University; Xia Liu, Emory University; Ashfaqul Alam, University of Kentucky; Keqiang Ye, Emory University
• Language: English
• Date: 2020-07
• Publisher: SCIENCE ADVANCES
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors, some rights reserved
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.aba0466
• Title of Journal or Parent Work: Sci Adv
• Volume: 6
• Issue: 31
• Grant/Funding Information: This work is supported by a grant from the NIH (RF1, AG051538; RO1, NS105982) to K.Y. This study was supported in part by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities (P30NS055077). Further support was provided by the Georgia Clinical and Translational Science Alliance of the National Institutes of Health under award number UL1TR002378.
• Keywords: CCAAT/enhancer binding proteins; microbiota; Alzheimer’s disease; β-amyloid precursor protein; Antibiotic treatment; β/asparagine endopeptidase; brain disorders; Tau; gut-brain axis
• Research Categories: Biology, Neuroscience; Psychology, Cognitive; Health Sciences, Pharmacology

Abstract

The gut-brain axis is bidirectional, and gut microbiota influence brain disorders including Alzheimer's disease (AD). CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling spatiotemporally mediates AD pathologies in the brain via cleaving both β-amyloid precursor protein and Tau. We show that gut dysbiosis occurs in 5xFAD mice, and is associated with escalation of the C/EBPβ/AEP pathway in the gut with age. Unlike that of aged wild-type mice, the microbiota of aged 3xTg mice accelerate AD pathology in young 3xTg mice, accompanied by active C/EBPβ/AEP signaling in the brain. Antibiotic treatment diminishes this signaling and attenuates amyloidogenic processes in 5xFAD, improving cognitive functions. The prebiotic R13 inhibits this pathway and suppresses amyloid aggregates in the gut. R13-induced Lactobacillus salivarius antagonizes the C/EBPβ/AEP axis, mitigating gut leakage and oxidative stress. Our findings support the hypothesis that C/EBPβ/AEP signaling is activated by gut dysbiosis, implicated in AD pathologies in the gut.