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Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer’s disease pathology in mouse models of Alzheimer’s disease

An imbalance in the circulatory and organ-specific renin-angiotensin system (RAS) pathways is associated with age-related dysfunction and disease including cardiovascular burden and more recently Alzheimer’s disease (AD). It is currently unclear whether an age-associated imbalance in components of t...

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Autores principales: MacLachlan, Robert, Evans, Charles E., Chai, Siew Yeen, Good, Mark A., Kehoe, Patrick Gavin, Miners, J. Scott
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997187/
https://www.ncbi.nlm.nih.gov/pubmed/36911263
http://dx.doi.org/10.1016/j.nbas.2022.100062
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author MacLachlan, Robert
Evans, Charles E.
Chai, Siew Yeen
Good, Mark A.
Kehoe, Patrick Gavin
Miners, J. Scott
author_facet MacLachlan, Robert
Evans, Charles E.
Chai, Siew Yeen
Good, Mark A.
Kehoe, Patrick Gavin
Miners, J. Scott
author_sort MacLachlan, Robert
collection PubMed
description An imbalance in the circulatory and organ-specific renin-angiotensin system (RAS) pathways is associated with age-related dysfunction and disease including cardiovascular burden and more recently Alzheimer’s disease (AD). It is currently unclear whether an age-associated imbalance in components of the RAS within the brain precedes the onset of AD or whether a RAS imbalance is associated with the onset of disease pathology and cognitive decline. Angiotensin-converting enzyme-1 (ACE-1) and -2 (ACE-2) protein (ELISA) and enzyme activity (FRET assay), markers of the classical and counter-regulatory RAS axis respectively, and Ang-II and Ang-(1–7) peptide levels (ELISA), were measured in the left cortex across four transgenic AD mouse models of amyloid pathology (5xFAD – 2, 6, and 12 months of age; Apd9 – 3-4, 12, and 18 months of age; Tg2576 – 3-4 and 24 months of age; and PDAPP – 3-4, 7, 11, 15, and 18 months of age) and littermate wild-type (WT) controls. ACE-1 level, and enzyme activity, was unaltered in relation to age in WT mice and across all four models. In contrast, ACE-2 level and enzyme activity, was reduced and Ang-II increased with ageing in both WT animals and disease models. The changes in ACE-2 and Ang-II in AD models mirrored WT mice, except for the 5xFAD model, when the reduction in ACE-2 (and elevated Ang-II) was observed at a younger age. These data indicate an age-related dysregulation of brain RAS is likely to be driven by a reduction in ACE-2. The reduction in ACE-2 occurs at a young age, coinciding with early pathological changes and the initial deposition of Aβ, and preceding neuronal loss and cognitive decline, in the transgenic AD models. However, the age-related loss was mirrored in WT mice suggesting that the change was independent of pathological Aβ deposition.
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spelling pubmed-99971872023-03-09 Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer’s disease pathology in mouse models of Alzheimer’s disease MacLachlan, Robert Evans, Charles E. Chai, Siew Yeen Good, Mark A. Kehoe, Patrick Gavin Miners, J. Scott Aging Brain Article An imbalance in the circulatory and organ-specific renin-angiotensin system (RAS) pathways is associated with age-related dysfunction and disease including cardiovascular burden and more recently Alzheimer’s disease (AD). It is currently unclear whether an age-associated imbalance in components of the RAS within the brain precedes the onset of AD or whether a RAS imbalance is associated with the onset of disease pathology and cognitive decline. Angiotensin-converting enzyme-1 (ACE-1) and -2 (ACE-2) protein (ELISA) and enzyme activity (FRET assay), markers of the classical and counter-regulatory RAS axis respectively, and Ang-II and Ang-(1–7) peptide levels (ELISA), were measured in the left cortex across four transgenic AD mouse models of amyloid pathology (5xFAD – 2, 6, and 12 months of age; Apd9 – 3-4, 12, and 18 months of age; Tg2576 – 3-4 and 24 months of age; and PDAPP – 3-4, 7, 11, 15, and 18 months of age) and littermate wild-type (WT) controls. ACE-1 level, and enzyme activity, was unaltered in relation to age in WT mice and across all four models. In contrast, ACE-2 level and enzyme activity, was reduced and Ang-II increased with ageing in both WT animals and disease models. The changes in ACE-2 and Ang-II in AD models mirrored WT mice, except for the 5xFAD model, when the reduction in ACE-2 (and elevated Ang-II) was observed at a younger age. These data indicate an age-related dysregulation of brain RAS is likely to be driven by a reduction in ACE-2. The reduction in ACE-2 occurs at a young age, coinciding with early pathological changes and the initial deposition of Aβ, and preceding neuronal loss and cognitive decline, in the transgenic AD models. However, the age-related loss was mirrored in WT mice suggesting that the change was independent of pathological Aβ deposition. Elsevier 2022-12-28 /pmc/articles/PMC9997187/ /pubmed/36911263 http://dx.doi.org/10.1016/j.nbas.2022.100062 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
MacLachlan, Robert
Evans, Charles E.
Chai, Siew Yeen
Good, Mark A.
Kehoe, Patrick Gavin
Miners, J. Scott
Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer’s disease pathology in mouse models of Alzheimer’s disease
title Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer’s disease pathology in mouse models of Alzheimer’s disease
title_full Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer’s disease pathology in mouse models of Alzheimer’s disease
title_fullStr Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer’s disease pathology in mouse models of Alzheimer’s disease
title_full_unstemmed Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer’s disease pathology in mouse models of Alzheimer’s disease
title_short Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer’s disease pathology in mouse models of Alzheimer’s disease
title_sort age-related reduction in brain ace-2 is not exacerbated by alzheimer’s disease pathology in mouse models of alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997187/
https://www.ncbi.nlm.nih.gov/pubmed/36911263
http://dx.doi.org/10.1016/j.nbas.2022.100062
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