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. ORCID: https://orcid.org/0000-0002-1824-1203, Kehoe, Patrick Gavin and Miners, J. Scott 2023. Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer?s disease pathology in mouse models of Alzheimer?s disease. Aging Brain 3 , 100062. 10.1016/j.nbas.2022.100062

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Psychology
Publisher:	Elsevier
ISSN:	2589-9589
Date of First Compliant Deposit:	9 January 2023
Date of Acceptance:	20 December 2022
Last Modified:	03 May 2023 15:14
URI:	https://orca.cardiff.ac.uk/id/eprint/155596

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