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Intra‐gastrointestinal amyloid‐β1–42 oligomers perturb enteric function and induce Alzheimer's disease pathology

KEY POINTS: Alzheimer's disease (AD) patients and transgenic mice have beta‐amyloid (Aβ) aggregation in the gastrointestinal (GI) tract. It is possible that Aβ from the periphery contributes to the load of Aβ in the brain, as Aβ has prion‐like properties. The present investigations demonstrate...

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Autores principales: Sun, Yayi, Sommerville, Nerina R., Liu, Julia Yuen Hang, Ngan, Man Piu, Poon, Daniel, Ponomarev, Eugene D., Lu, Zengbing, Kung, Jeng S. C., Rudd, John A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586845/
https://www.ncbi.nlm.nih.gov/pubmed/32617993
http://dx.doi.org/10.1113/JP279919
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author Sun, Yayi
Sommerville, Nerina R.
Liu, Julia Yuen Hang
Ngan, Man Piu
Poon, Daniel
Ponomarev, Eugene D.
Lu, Zengbing
Kung, Jeng S. C.
Rudd, John A.
author_facet Sun, Yayi
Sommerville, Nerina R.
Liu, Julia Yuen Hang
Ngan, Man Piu
Poon, Daniel
Ponomarev, Eugene D.
Lu, Zengbing
Kung, Jeng S. C.
Rudd, John A.
author_sort Sun, Yayi
collection PubMed
description KEY POINTS: Alzheimer's disease (AD) patients and transgenic mice have beta‐amyloid (Aβ) aggregation in the gastrointestinal (GI) tract. It is possible that Aβ from the periphery contributes to the load of Aβ in the brain, as Aβ has prion‐like properties. The present investigations demonstrate that Aβ injected into the GI tract of ICR mice is internalised into enteric cholinergic neurons; at 1 month, administration of Aβ into the body of the stomach and the proximal colon was observed to partly redistribute to the fundus and jejunum; at 1 year, vagal and cerebral β‐amyloidosis was present, and mice exhibited GI dysfunction and cognitive deficits. These data reveal a previously undiscovered mechanism that potentially contributes to the development of AD. ABSTRACT: Alzheimer's disease (AD) is the most common age‐related cause of dementia, characterised by extracellular beta‐amyloid (Aβ) plaques and intracellular phosphorylated tau tangles in the brain. Aβ deposits have also been observed in the gastrointestinal (GI) tract of AD patients and transgenic mice, with overexpression of amyloid precursor protein. In the present studies, we investigate whether intra‐GI administration of Aβ can potentially induce amyloidosis in the central nervous system (CNS) and AD‐related pathology such as dementia. We micro‐injected Aβ1–42 oligomers (4 μg per site, five sites) or vehicle (saline, 5 μl) into the gastric wall of ICR mice under general anaesthesia. Immunofluorescence staining and in vivo imaging showed that HiLyte Fluor 555‐labelled Aβ1–42 had migrated within 3 h via the submucosa to nearby areas and was internalised into cholinergic neurons. At 1 month, HiLyte Fluor 555‐labelled Aβ1–42 in the body of the stomach and proximal colon had partly re‐distributed to the fundus and jejunum. At 1 year, the jejunum showed functional alterations in neuromuscular coupling (P < 0.001), and Aβ deposits were present in the vagus and brain, with animals exhibiting cognitive impairments in the Y‐maze spontaneous alteration test (P < 0.001) and the novel object recognition test (P < 0.001). We found that enteric Aβ oligomers induce an alteration in gastric function, amyloidosis in the CNS, and AD‐like dementia via vagal mechanisms. Our results suggest that Aβ load is likely to occur initially in the GI tract and may translocate to the brain, opening the possibility of new strategies for the early diagnosis and prevention of AD.
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spelling pubmed-75868452020-10-30 Intra‐gastrointestinal amyloid‐β1–42 oligomers perturb enteric function and induce Alzheimer's disease pathology Sun, Yayi Sommerville, Nerina R. Liu, Julia Yuen Hang Ngan, Man Piu Poon, Daniel Ponomarev, Eugene D. Lu, Zengbing Kung, Jeng S. C. Rudd, John A. J Physiol Alimentary KEY POINTS: Alzheimer's disease (AD) patients and transgenic mice have beta‐amyloid (Aβ) aggregation in the gastrointestinal (GI) tract. It is possible that Aβ from the periphery contributes to the load of Aβ in the brain, as Aβ has prion‐like properties. The present investigations demonstrate that Aβ injected into the GI tract of ICR mice is internalised into enteric cholinergic neurons; at 1 month, administration of Aβ into the body of the stomach and the proximal colon was observed to partly redistribute to the fundus and jejunum; at 1 year, vagal and cerebral β‐amyloidosis was present, and mice exhibited GI dysfunction and cognitive deficits. These data reveal a previously undiscovered mechanism that potentially contributes to the development of AD. ABSTRACT: Alzheimer's disease (AD) is the most common age‐related cause of dementia, characterised by extracellular beta‐amyloid (Aβ) plaques and intracellular phosphorylated tau tangles in the brain. Aβ deposits have also been observed in the gastrointestinal (GI) tract of AD patients and transgenic mice, with overexpression of amyloid precursor protein. In the present studies, we investigate whether intra‐GI administration of Aβ can potentially induce amyloidosis in the central nervous system (CNS) and AD‐related pathology such as dementia. We micro‐injected Aβ1–42 oligomers (4 μg per site, five sites) or vehicle (saline, 5 μl) into the gastric wall of ICR mice under general anaesthesia. Immunofluorescence staining and in vivo imaging showed that HiLyte Fluor 555‐labelled Aβ1–42 had migrated within 3 h via the submucosa to nearby areas and was internalised into cholinergic neurons. At 1 month, HiLyte Fluor 555‐labelled Aβ1–42 in the body of the stomach and proximal colon had partly re‐distributed to the fundus and jejunum. At 1 year, the jejunum showed functional alterations in neuromuscular coupling (P < 0.001), and Aβ deposits were present in the vagus and brain, with animals exhibiting cognitive impairments in the Y‐maze spontaneous alteration test (P < 0.001) and the novel object recognition test (P < 0.001). We found that enteric Aβ oligomers induce an alteration in gastric function, amyloidosis in the CNS, and AD‐like dementia via vagal mechanisms. Our results suggest that Aβ load is likely to occur initially in the GI tract and may translocate to the brain, opening the possibility of new strategies for the early diagnosis and prevention of AD. John Wiley and Sons Inc. 2020-07-06 2020-10-01 /pmc/articles/PMC7586845/ /pubmed/32617993 http://dx.doi.org/10.1113/JP279919 Text en © 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Alimentary
Sun, Yayi
Sommerville, Nerina R.
Liu, Julia Yuen Hang
Ngan, Man Piu
Poon, Daniel
Ponomarev, Eugene D.
Lu, Zengbing
Kung, Jeng S. C.
Rudd, John A.
Intra‐gastrointestinal amyloid‐β1–42 oligomers perturb enteric function and induce Alzheimer's disease pathology
title Intra‐gastrointestinal amyloid‐β1–42 oligomers perturb enteric function and induce Alzheimer's disease pathology
title_full Intra‐gastrointestinal amyloid‐β1–42 oligomers perturb enteric function and induce Alzheimer's disease pathology
title_fullStr Intra‐gastrointestinal amyloid‐β1–42 oligomers perturb enteric function and induce Alzheimer's disease pathology
title_full_unstemmed Intra‐gastrointestinal amyloid‐β1–42 oligomers perturb enteric function and induce Alzheimer's disease pathology
title_short Intra‐gastrointestinal amyloid‐β1–42 oligomers perturb enteric function and induce Alzheimer's disease pathology
title_sort intra‐gastrointestinal amyloid‐β1–42 oligomers perturb enteric function and induce alzheimer's disease pathology
topic Alimentary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586845/
https://www.ncbi.nlm.nih.gov/pubmed/32617993
http://dx.doi.org/10.1113/JP279919
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