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

Chun Chen; Eun Hee Ahn; Seong Su Kang; Xia Liu; Ashfaqul Alam; Keqiang Ye

doi:10.1126/sciadv.aba0466

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

Chun Chen
, Eun Hee Ahn
, Seong Su Kang
, Xia Liu
, Ashfaqul Alam
, Keqiang Ye

Microbiology, Immunology, and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

203 Scopus citations

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.

Original language	English
Article number	eaba0466
Journal	Science advances
Volume	6
Issue number	31
DOIs	https://doi.org/10.1126/sciadv.aba0466
State	Published - Jul 2020

Bibliographical note

Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved.

Funding

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. Author contributions: K.Y. conceived the project designed the experiments

Funders	Funder number
National Institutes of Health (NIH)	AG051538, UL1TR002378, NS105982
National Institutes of Health (NIH)
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	P30NS055077
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council
Emory University School of Medicine

ASJC Scopus subject areas

General

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title = "Gut dysbiosis contributes to amyloid pathology, associated with C/EBPΒ/AEP signaling activation in Alzheimer's disease mouse model",

abstract = "The gut-brain axis is bidirectional, and gut microbiota influence brain disorders including Alzheimer{\textquoteright}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.",

author = "Chun Chen and Ahn, \{Eun Hee\} and Kang, \{Seong Su\} and Xia Liu and Ashfaqul Alam and Keqiang Ye",

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language = "English",

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AU - Alam, Ashfaqul

AU - Ye, Keqiang

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AB - 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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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