A longitudinal genomic analysis of the brain renin angiotensin system in a novel mouse model of Alzheimer’s Disease (AD)

Background: Clinical and rodent studies suggest that the brain renin-angiotensin system (bRAS) may play a role in Alzheimer’s disease (AD) pathology and cognitive decline. This study utilized recently developed novel transgenic AD-BXD mouse strains, designed to enhance understanding of genetic diversity, in susceptibility and resiliency factors, in AD. Methods: B6-5XFAD mice were crossed with 28 BXD strains to generate a population of AD-BXDs (Neuner et al, 2019;). Bulk RNA sequencing (RNAseq) data from the hippocampus of male and female mice at 6 and 14 months of age were evaluated for bRAS-related protein gene expression changes (GEO accession numbers: GSE101144, GSE119215, and GSE119408). Comparisons between AD gene carriers (AD-BXD, n = 135) vs noncarrier littermates (Ntg-BXD, n = 157) assessed differential expression of bRAS-related genes; Agtr1b, AP-A, Rnpep, Ace, Agtr1a, Agtr2, Ren, Agt, AP-N, Ace2, Atp6ap2, Agtrap, Adam17, MasR, Lnpep, and Nr3c2. Single-nucleus RNA sequencing data from the Religious Orders Study and Memory and Aging Project (ROS/MAP; PMID: 37774677; n = 427) was also used. Parallel comparison of bRAS-related genes were analyzed in amyloid+ and amyloid- populations from the human ROS/MAP data base. Results: Expression of the primary receptor subtypes of the bRAS, Agtr1 and Agtr2, were unchanged, however a significant main effect of genotype was observed in the expression of the mineralocorticoid receptor (Nr3c2), Mas receptor (MasR), pro-renin receptor (Atp6ap2), and the angiotensin type IV receptor (Lnpep) were significantly downregulated in AD-BXD mice compared to Ntg-BXD mice, suggesting a potential moderation of function of the bRAS in AD mice. A significant main effect of sex was observed in the expression of Adam17, MasR, Lnpep, and Nr3c2. Interaction analysis revealed a significant genotype x age interaction for the expression of Agtrap, Adam17, and MasR, indicating potential age-specific roles in AD pathophysiology. In human cortical tissue, expression of MasR and Atp6ap2 was also significantly decreased in individuals with amyloid+ status (MasR: -0.02 logFC, adj-p = 0.03; Atp6ap2: -0.03 logFC, adj-p = 0.005). Conclusions: Our findings reveal significant changes gene expression of bRAS related receptors and regulatory proteins in a mouse model exhibiting genetic, transcriptomic, and phenotypic diversity. This study provides valuable insights into the regulatory mechanisms of the bRAS in AD pathology and may provide novel therapeutic targets for preventing or delaying the onset and progression of AD. NIH - NIA 1R21AG086859-01 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.