Altered Gene Expression Within the Renin–Angiotensin System in Normal Aging and Dementia

Hannah m Tayler, Robert Maclachlan, Özge Güzel, Robert a Fisher, Olivia a Skrobot, Mohamed a Abulfadl, Patrick g Kehoe*, J Scott Miners*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

The renin–angiotensin system (RAS) is dysregulated in Alzheimer’s disease (AD). In this study, we have explored the hypothesis that an ­age-­related imbalance in brain RAS is a trigger for RAS dysregulation in AD. We characterized RAS gene expression in the frontal cortex from (i) a cohort of normal aging (n = 99, age range = 19–96 years) and (ii) a case–control cohort (n = 209) including AD (n = 66), mixed dementia (VaD + AD; n = 50), pure vascular dementia (VaD; n = 42), and age-matched controls (n = 51). The AD, mixed dementia, and age-matched controls were further stratified by Braak tangle stage (BS): BS0–II (n = 48), BSIII–IV (n = 44), and BSV–VI (n = 85). Gene expression was calculated by quantitative PCR (qPCR) for ACE1, AGTR1, AGTR2, ACE2, LNPEP, and MAS1 using the 2−∆∆Cq method, after adjustment for reference genes (RPL13 and UBE2D2) and cell-specific calibrator genes (NEUN, GFAP, PECAM). ACE1 and AGTR1, markers of classical RAS signaling, and AGTR2 gene expression were elevated in normal aging and gene expression in markers of protective downstream regulatory RAS signaling, including ACE2, MAS1, and LNPEP, were unchanged. In AD and mixed dementia, AGTR1 and AGTR2 gene expression were elevated in BSIII–IV and BSV–VI, respectively. MAS1 gene expression was reduced at BSV–VI and was inversely related to parenchymal Aβ and tau load. LNPEP gene expression was specifically elevated in VaD. These data provide novel insights into RAS signaling in normal aging and dementia.
Original languageEnglish
Article numberglad241
Number of pages10
JournalJournals of Gerontology, Series A
Volume79
Issue number1
Early online date9 Oct 2023
DOIs
Publication statusPublished - 1 Jan 2024

Bibliographical note

Publisher Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.

Funding Information: We would like to thank the South West Dementia Brain Bank (SWDBB), their donors, and donors families for providing brain tissue for this study. The SWDBB is part of the Brains for Dementia Research program, jointly funded by Alzheimer’s Research UK and Alzheimer’s Society and is supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) and the Medical Research Council. Tissue for this study was also provided by the Newcastle Brain Tissue Resource which is funded in part by a grant from the UK Medical Research Council (G0400074), by NIHR Newcastle Biomedical Research Centre and Unit awarded to the Newcastle upon Tyne NHS Foundation Trust and Newcastle University, and as part of the Brains for Dementia Research Programme jointly funded by Alzheimer’s Research UK and Alzheimer’s Society. We also thank the donors for brain samples obtained from the Edinburgh Brain and Tissue Bank.

Structured keywords

  • Dementia Research Group

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