Blockade of Brain Angiotensin II AT1 Receptor Ameliorates Inflammation, YKL-40, and ROS Production from Astrocytes

Abstract ID 130054 Poster Board 140 Alzheimer's Disease (AD) is the most common cause of dementia. AD patients had increased extracellular amyloid β plaques and intracellular hyperphosphorylated tau (p-tau) in neurons. YKL-40 is an inflammatory biomarker of AD. Recent studies have shown an association between the Renin-Angiotensin System (RAS) and AD. The involvement of RAS has been mediated through Angiotensin II (AngII), which is overexpressed in aging brains. However, the exact mechanism of how AngII contributes to AD is unknown. Thus, we hypothesize that AngII increases brain inflammation and YKL-40 production from astrocytes and increases ROS generation by its AT1 receptor (AT1R). In the human astroglia cell line, SVGp12, treatment with AngII increased YKL-40 production by 40% (p<0.05, n = 4), and the AT1R antagonist, Losartan, blocked this effect. In addition, the effects of AngII on pro-inflammatory cytokines were studied. AngII upregulated the gene expression of IL-6 (p < 0.01, n = 4) and increased IL-6 concentrations by 68% (p<0.05, n = 4), as measured by ELISA. Losartan blocked the changes in IL-6. Also, AngII induced the production of TNF- α, increasing its concentration by 76% (p<0.05, n = 4), an increase that Losartan also blocked. We then quantified reactive oxygen species (ROS) production by using MUSE Oxidative Stress assay. In SVGp12 cells, ROS production was significantly increased by AngII (p<0.05, n = 4), and treatment with Losartan blunted their production (p<0.05, n = 4). These results suggest that AngII can activate astroglia cell pro-inflammatory responses and increase ROS production, which may contribute to the pathophysiology of CNS inflammation and AD. AT1R antagonists could be considered a possible therapeutic agent for AD due to its protective role against Ang II's effects.