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Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice
Amyloid plaques in Alzheimer’s disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (Aβ) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the Aβ burden prior to brain, high...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084806/ https://www.ncbi.nlm.nih.gov/pubmed/32138161 http://dx.doi.org/10.3390/ijms21051711 |
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author | Honarpisheh, Pedram Reynolds, Caroline R. Blasco Conesa, Maria P. Moruno Manchon, Jose F. Putluri, Nagireddy Bhattacharjee, Meenakshi B. Urayama, Akihiko McCullough, Louise D. Ganesh, Bhanu P. |
author_facet | Honarpisheh, Pedram Reynolds, Caroline R. Blasco Conesa, Maria P. Moruno Manchon, Jose F. Putluri, Nagireddy Bhattacharjee, Meenakshi B. Urayama, Akihiko McCullough, Louise D. Ganesh, Bhanu P. |
author_sort | Honarpisheh, Pedram |
collection | PubMed |
description | Amyloid plaques in Alzheimer’s disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (Aβ) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the Aβ burden prior to brain, highlighting gut–brain axis (GBA) interaction in neurodegenerative disorders. We used pre-symptomatic (6-months) and symptomatic (15-months) Tg2576 mouse model of AD compared to their age-matched littermate WT control. We identified that dysfunction of intestinal epithelial barrier (IEB), dysregulation of absorption, and vascular Aβ deposition in the IEB occur before cerebral Aβ aggregation is detectible. These changes in the GBA were associated with elevated inflammatory plasma cytokines including IL-9, VEGF and IP-10. In association with reduced cerebral myelin tight junction proteins, we identified reduced levels of systemic vitamin B12 and decrease cubilin, an intestinal B12 transporter, after the development of cerebral Aβ pathology. Lastly, we report Aβ deposition in the intestinal autopsy from AD patients with confirmed cerebral Aβ pathology that is not present in intestine from non-AD controls. Our data provide evidence that gut dysfunction occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve the early manipulation of gut physiology and its microbiota. |
format | Online Article Text |
id | pubmed-7084806 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70848062020-03-24 Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice Honarpisheh, Pedram Reynolds, Caroline R. Blasco Conesa, Maria P. Moruno Manchon, Jose F. Putluri, Nagireddy Bhattacharjee, Meenakshi B. Urayama, Akihiko McCullough, Louise D. Ganesh, Bhanu P. Int J Mol Sci Article Amyloid plaques in Alzheimer’s disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (Aβ) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the Aβ burden prior to brain, highlighting gut–brain axis (GBA) interaction in neurodegenerative disorders. We used pre-symptomatic (6-months) and symptomatic (15-months) Tg2576 mouse model of AD compared to their age-matched littermate WT control. We identified that dysfunction of intestinal epithelial barrier (IEB), dysregulation of absorption, and vascular Aβ deposition in the IEB occur before cerebral Aβ aggregation is detectible. These changes in the GBA were associated with elevated inflammatory plasma cytokines including IL-9, VEGF and IP-10. In association with reduced cerebral myelin tight junction proteins, we identified reduced levels of systemic vitamin B12 and decrease cubilin, an intestinal B12 transporter, after the development of cerebral Aβ pathology. Lastly, we report Aβ deposition in the intestinal autopsy from AD patients with confirmed cerebral Aβ pathology that is not present in intestine from non-AD controls. Our data provide evidence that gut dysfunction occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve the early manipulation of gut physiology and its microbiota. MDPI 2020-03-03 /pmc/articles/PMC7084806/ /pubmed/32138161 http://dx.doi.org/10.3390/ijms21051711 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Honarpisheh, Pedram Reynolds, Caroline R. Blasco Conesa, Maria P. Moruno Manchon, Jose F. Putluri, Nagireddy Bhattacharjee, Meenakshi B. Urayama, Akihiko McCullough, Louise D. Ganesh, Bhanu P. Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice |
title | Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice |
title_full | Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice |
title_fullStr | Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice |
title_full_unstemmed | Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice |
title_short | Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice |
title_sort | dysregulated gut homeostasis observed prior to the accumulation of the brain amyloid-β in tg2576 mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084806/ https://www.ncbi.nlm.nih.gov/pubmed/32138161 http://dx.doi.org/10.3390/ijms21051711 |
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