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

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Abstract

This study reveals the contribution of gut bacteria to Alzheimer’s disease.

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.

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Inflammation and Alzheimer's disease.

H Akiyama, S. Barger, S Barnum … (2000)

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

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Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Min-Soo Kim, Yoonhee Kim, Hyunjung Choi … (2019)

Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive. Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLP APT ) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis. Composition of the gut microbiota in ADLP APT mice differed from that of healthy wild-type (WT) mice. Besides, ADLP APT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLP APT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLP APT recipient mice. These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLP APT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

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Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway

John Haran, Shakti K Bhattarai, Sage Foley … (2019)

Studies of the intestinal microbiome and AD have demonstrated associations with microbiome composition at the genus level among matched cohorts. We move this body of literature forward by more deeply investigating microbiome composition via metagenomics and by comparing AD patients against those without dementia and with other dementia types. We also exploit machine learning approaches that combine both metagenomic and clinical data. Finally, our functional studies using stool samples from elders demonstrate how the c microbiome of AD elders can affect intestinal health via dysregulation of the P-glycoprotein pathway. P-glycoprotein dysregulation contributes directly to inflammatory disorders of the intestine. Since AD has been long thought to be linked to chronic bacterial infections as a possible etiology, our findings therefore fill a gap in knowledge in the field of AD research by identifying a nexus between the microbiome, loss of intestinal homeostasis, and inflammation that may underlie this neurodegenerative disorder.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: July 2020

Publication date (Electronic): 29 July 2020

Volume: 6

Issue: 31

Electronic Location Identifier: eaba0466

Affiliations

[1 ]Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.

[2 ]Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536, USA.

Author notes

[* ]Corresponding author. Email: kye@ 123456emory.edu (K.Y.); m.ashfaqul.alam@ 123456uky.edu (A.A.)

Author information

Chun Chen http://orcid.org/0000-0003-3041-3263

Eun Hee Ahn http://orcid.org/0000-0002-1833-6720

Xia Liu http://orcid.org/0000-0002-0180-2166

Ashfaqul Alam http://orcid.org/0000-0002-9260-3372

Keqiang Ye http://orcid.org/0000-0002-7657-8154

Article

Publisher ID: aba0466

DOI: 10.1126/sciadv.aba0466

PMC ID: 7439296

PubMed ID: 32832679

SO-VID: 30b7f523-e4bb-4ce8-aba8-0a1a83524c17

Copyright © Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 30 October 2019

Date accepted : 15 June 2020

Funding

Funded by: doi http://dx.doi.org/10.13039/100000052, NIH Office of the Director;

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

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Functional role of amyloid

Most cited references 25

Inflammation and Alzheimer's disease.

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway

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