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

• Published in: The journals of gerontology. Series A, Biological sciences and medical sciences Biological sciences and medical sciences, 2024-01, Vol.79 (1)
• Main Authors: Tayler, Hannah M, MacLachlan, Robert, Güzel, Özge, Fisher, Robert A, Skrobot, Olivia A, Abulfadl, Mohamed A, Kehoe, Patrick G, Miners, J Scott
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Aging; Aging - genetics; Alzheimer Disease - genetics; Alzheimer's disease; Angiotensin; Angiotensin-Converting Enzyme 2; Cortex (frontal); Dementia; Dementia disorders; Gene Expression; Genes; Glial fibrillary acidic protein; Humans; Mixed Dementias; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neurodegenerative diseases; Peptidyl-Dipeptidase A - metabolism; Ras protein; Renin; Renin-Angiotensin System - genetics; Ribosomal Proteins - genetics; Tau protein; THE JOURNAL OF GERONTOLOGY: Biological Sciences; Vascular dementia; β-Amyloid
• ISSN: 1079-5006; 1758-535X
• DOI: 10.1093/gerona/glad241

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.