Renin-Angiotensin System Alterations in the Human Alzheimer’s Disease Brain

Article type: Research Article

Authors: Ismael, Saifudeen^{a; 1} | Mirzahosseini, Golnoush^{a; b; 1} | Ahmed, Heba A.^a | Yoo, Arum^a | Kassan, Modar^c | Malik, Kafait U.^{d; e} | Ishrat, Tauheed^{a; b; e; *}

Affiliations: [a] Departments of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA | [b] Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA | [c] Departments of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA | [d] Departments of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA | [e] Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, USA

Correspondence: [*] Correspondence to: Tauheed Ishrat, PhD, University of Tennessee Health Science Center, College of Medicine, Department of Anatomy and Neurobiology, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN 38163, USA. Tel.: +1 901 448 2178; Fax: +1 901 448 7193; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Understanding Alzheimer’s disease (AD) in terms of its various pathophysiological pathways is essential to unravel the complex nature of the disease process and identify potential therapeutic targets. The renin-angiotensin system (RAS) has been implicated in several brain diseases, including traumatic brain injury, ischemic stroke, and AD. Objective:This study was designed to evaluate the protein expression levels of RAS components in postmortem cortical and hippocampal brain samples obtained from AD versus non-AD individuals. Methods:We analyzed RAS components in the cortex and hippocampus of postmortem human brain samples by western blotting and immunohistochemical techniques in comparison with age-matched non-demented controls. Results:The expression of AT1R increased in the hippocampus, whereas AT2R expression remained almost unchanged in the cortical and hippocampal regions of AD compared to non-AD brains. The Mas receptor was downregulated in the hippocampus. We also detected slight reductions in ACE-1 protein levels in both the cortex and hippocampus of AD brains, with minor elevations in ACE-2 in the cortex. We did not find remarkable differences in the protein levels of angiotensinogen and Ang II in either the cortex or hippocampus of AD brains, whereas we observed a considerable increase in the expression of brain-derived neurotrophic factor in the hippocampus. Conclusion:The current findings support the significant contribution of RAS components in AD pathogenesis, further suggesting that strategies focusing on the AT1R and AT2R pathways may lead to novel therapies for the management of AD.

Keywords: Alzheimer’s disease, angiotensin-converting enzyme, angiotensin type 1 receptor, angiotensin type 2 receptor, renin-angiotensin system

DOI: 10.3233/JAD-215051

Journal: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1473-1484, 2021