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

Min Soo Kim, Yoonhee Kim, Hyunjung Choi, Woojin Kim, Sumyung Park, Dongjoon Lee, Dong Kyu Kim, Haeng Jun Kim, Hayoung Choi, Dong Wook Hyun, June Young Lee, Eun Young Choi, Dong Sup Lee, Jin Woo Bae, Inhee Mook-Jung

Research output: Contribution to journalArticle

Abstract

Objective 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. Design 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. Results 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. Conclusion 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.

Original languageEnglish
Pages (from-to)283-294
Number of pages12
JournalGut
Volume69
Issue number2
DOIs
StatePublished - 1 Feb 2020

Fingerprint

Microbiota
Amyloid
Alzheimer Disease
Animal Models
Pathology
Neurofibrillary Tangles
Amyloid Plaques
Memory Disorders
Brain
Tauopathies
Gene Expression
Gliosis
Neuroglia
Transgenic Mice
APT
Monocytes
Permeability
Blood Cells
Homeostasis
Macrophages

Keywords

  • Alzheimer's disease
  • beta-amyloid
  • fecal microbiota transfer
  • gut microbiota
  • hyperphosphorylated tau

Cite this

Kim, Min Soo ; Kim, Yoonhee ; Choi, Hyunjung ; Kim, Woojin ; Park, Sumyung ; Lee, Dongjoon ; Kim, Dong Kyu ; Kim, Haeng Jun ; Choi, Hayoung ; Hyun, Dong Wook ; Lee, June Young ; Choi, Eun Young ; Lee, Dong Sup ; Bae, Jin Woo ; Mook-Jung, Inhee. / Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model. In: Gut. 2020 ; Vol. 69, No. 2. pp. 283-294.
@article{839f22d163614fd695c73b0a6fe729c5,
title = "Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model",
abstract = "Objective 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. Design 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. Results 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. Conclusion 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.",
keywords = "Alzheimer's disease, beta-amyloid, fecal microbiota transfer, gut microbiota, hyperphosphorylated tau",
author = "Kim, {Min Soo} and Yoonhee Kim and Hyunjung Choi and Woojin Kim and Sumyung Park and Dongjoon Lee and Kim, {Dong Kyu} and Kim, {Haeng Jun} and Hayoung Choi and Hyun, {Dong Wook} and Lee, {June Young} and Choi, {Eun Young} and Lee, {Dong Sup} and Bae, {Jin Woo} and Inhee Mook-Jung",
year = "2020",
month = "2",
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Kim, MS, Kim, Y, Choi, H, Kim, W, Park, S, Lee, D, Kim, DK, Kim, HJ, Choi, H, Hyun, DW, Lee, JY, Choi, EY, Lee, DS, Bae, JW & Mook-Jung, I 2020, 'Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model', Gut, vol. 69, no. 2, pp. 283-294. https://doi.org/10.1136/gutjnl-2018-317431

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model. / Kim, Min Soo; Kim, Yoonhee; Choi, Hyunjung; Kim, Woojin; Park, Sumyung; Lee, Dongjoon; Kim, Dong Kyu; Kim, Haeng Jun; Choi, Hayoung; Hyun, Dong Wook; Lee, June Young; Choi, Eun Young; Lee, Dong Sup; Bae, Jin Woo; Mook-Jung, Inhee.

In: Gut, Vol. 69, No. 2, 01.02.2020, p. 283-294.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model

AU - Kim, Min Soo

AU - Kim, Yoonhee

AU - Choi, Hyunjung

AU - Kim, Woojin

AU - Park, Sumyung

AU - Lee, Dongjoon

AU - Kim, Dong Kyu

AU - Kim, Haeng Jun

AU - Choi, Hayoung

AU - Hyun, Dong Wook

AU - Lee, June Young

AU - Choi, Eun Young

AU - Lee, Dong Sup

AU - Bae, Jin Woo

AU - Mook-Jung, Inhee

PY - 2020/2/1

Y1 - 2020/2/1

N2 - Objective 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. Design 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. Results 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. Conclusion 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.

AB - Objective 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. Design 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. Results 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. Conclusion 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.

KW - Alzheimer's disease

KW - beta-amyloid

KW - fecal microbiota transfer

KW - gut microbiota

KW - hyperphosphorylated tau

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U2 - 10.1136/gutjnl-2018-317431

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