Age-associated changes in the renin-angiotensin system

: implications for future clinical trials

Abstract

Overactivity of the renin-angiotensin system (RAS), both systemically and within organs, is associated with ageing and cardiovascular diseases. Localised brain RAS is dysregulated in Alzheimer’s disease (AD). In this thesis, I investigated brain RAS signalling in normal ageing and AD in transgenic mouse models and human post-mortem brain tissue.
In mice, ACE-1, ACE-2, (ELISA) and enzyme activity (FRET-based activity assay), and Ang-II and Ang-(1-7) levels (ELISA), were measured at different ages corresponding to the onset of pathology and cognitive decline. In humans, RAS gene (RT-PCR), protein, and enzyme activities were measured in the frontal and temporal cortex in a normal ageing cohort (n=101, 19-80y) and an AD cohort (n=60), stratified according to Braak tangle stage (BS), as a proxy of disease stage.
In mice, ACE-2 declined with normal ageing across all four APP-transgenic models. Surprisingly, RAS markers were similar between transgenic and wild-type mice and were not exacerbated in-line with the onset of disease or cognitive decline (except for elevated ACE-2 activity and Ang-II levels at a younger age in the aggressive 5xFAD model).
In humans, an age- and disease-related dysregulation of RAS signalling was observed. The age-related imbalance was driven by cRAS overactivation and differed from RAS dysregulation in AD. Notably in AD, ACE-1 enzyme activity was induced in the early stages of disease (BS III-IV) and MAS1 and IRAP’s expressions (mediators of regulatory RAS signalling) were reduced.
In conclusion, (i) age-related changes in brain RAS differ between mice and humans, (ii) age-related changes in human brain RAS are driven by cRAS signalling (iii) AD-related changes in RAS include early induction of ACE-1 activity and a reduction in the expression of rRAS genes in late-stage AD. Overall, RAS in normal ageing differs from dysregulated RAS in AD, offering a potential novel therapeutic target in the early stages of AD.

Date of Award	9 May 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	J S Miners (Supervisor) & Patrick Gavin Kehoe (Supervisor)