Higher angiotensin II type 1 receptor (AT1R) levels and activity in the postmortem brains of older persons with Alzheimer's disease. (December 2021)

• Record Type: Journal Article
• Authors: Cosarderelioglu, Caglar; George, Claudene J; Marx‐Rattner, Ruth; Xue, Qian‐Li; Tian, Jing; Oh, Esther S; Ferrucci, Luigi; Bennett, David A.; Walston, Jeremy; Abadir, Peter
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.053001
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Alzheimer's disease (AD) is the most common cause of dementia. Although multiple potential etiologies have been proposed, no clear aging‐related etiological mechanisms have been identified. Renin Angiotensin system (RAS) is a hormonal system that is implicated in blood pressure control and has been suggested as a potential contributor to the development of AD. Here, using postmortem frontal cortex brain samples of age‐ and sex‐matched cognitively normal individuals (n=30) and AD patients (n=30), we sought to examine the brain specific RAS (b‐RAS) differences with AD and how these findings correlate with brain AD pathologies. Method: Samples were obtained from the Rush Memory and Aging Project. We measured angiotensinogen, renin, and ACE gene expression by qPCR and both gene expression and protein levels of Angiotensin II receptor type 1, 2, and 4 and their downstream signaling pathway (pERK, eNOS, and nNOS) by qPCR and Western blot. Brain cytokines (IL6, TNFα, IFNγ, and IL1β) and oxidative stress (OS) marker (protein carbonyl) as well as average paired helical filaments‐tau and β‐amyloid load were used as specific markers of AD pathology. Result: Our results demonstrate an increase in both gene and protein expression (2.47 folds p=0.01, median0.59 (range1.99) vs. 0.47 (1.95) p=0.03, respectively) and signaling activity (0.35 (11.41) vs. 0.04 (1.84), p<0.01) of AT1 R in AD. We have not observed any significant changes in other RAS components. Our data show that higher AT1 R levels correlate with OS (r=0.301 p=0.01) and β‐amyloid load (r=0.245 p=0.04), while higher pERK levels negatively correlate with MN (r=‐0.239 p=0.03) and positively correlate with total tangle (r=0.413 p<0.01) and amyloid (r=0.208 p=0.02) scores. Finally, mRNA, protein, and pERK levels of AT1 R were negatively correlated with global cognitive function (GCF) scores (r=‐0.216 p=0.05, r=‐0.258 p=0.02, r=‐0.376 p<0.01, respectively) and were associated with greater decline in GCF (r=0.265 p=0.02, r=0.223 p=0.04, respectively) in all subjects. Conclusion: This study highlights molecular changes in b‐RAS and offers insight into the association of these changes with brain pathology in AD. These findings can be important in shedding light on the benefits of RAS‐modulating drugs in AD.