Exploring the role of the renin angiotensin system in Alzheimer’s disease - investigations into genetic variations and neuropathology

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

The brain renin-angiotensin system (RAS) is imbalanced and associated with cognitive
impairment and disease pathology in Alzheimer's disease (AD). Angiotensin-converting
enzyme-1 (ACE1), a risk gene for AD, encodes ACE-1 that has diverging roles in AD where is
responsible for classical RAS (cRAS) overactivation (damaging) and degrading Aβ peptides
(protective). It is still unclear how genetic variation in ACE1 influences AD risk.
The major aim of this PhD was to investigate if an established ACE1 polymorphism linked to
AD risk was related to dysregulation of RAS and disease pathology in AD. In addition, two
SNPs in ACE2 (regulatory RAS signalling) and AGT (upstream cRAS signalling) were examined
to determine if they were similarly related to disease risk and pathology in AD.
Post-mortem brain tissue was obtained from the South West Dementia Brain Bank,
University of Bristol. Frontal and parietal cortex from AD (n=94), vascular dementia (n=20),
mixed AD/VaD (n=33) and age-matched controls (n=104) were studied. ACE1 (rs4343), ACE2
(rs4240157 and rs2285666) and AGT (rs4762 and rs699) polymorphisms were genotyped by
PCR. ACE-1 and ACE-2 were measured by ELISA and enzyme activity assays. AGT and
Angiotensin (II, III and 1-7) levels were measured by ELISA. RAS markers were assessed by
qPCR. Parenchymal Aβ and tau load were quantified by IHC and Aβ40/42 by ELISA.
ACE-1 was elevated, whereas ACE-2 was reduced, indicative of an imbalance of brain RAS in
AD. The protective ACE1 DD genotype was associated with elevated ACE-1 gene and protein
levels, higher total and N-domain ACE-1 enzyme activity, and reduced Aβ parenchymal load.
Inheritance of ACE2 and AGT were not associated with AD risk and did not influence RAS
signalling or disease pathology.
The study provides novel insights and continues to highlight the important role of ACE-1 as
a potential major contributor to disease risk and pathogenesis in AD.
Date of Award19 Mar 2024
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorPatrick Gavin Kehoe (Supervisor) & J S Miners (Supervisor)

Keywords

  • Alzheimer's disease
  • renin-angiotensin system
  • Dementia

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