Angiotensin II does not directly affect Aβ secretion or β-/γ-secretase activity via activation of angiotensin II type 1 receptor

Recent studies suggest that brain angiotensin II (Ang II), the major effector molecule of the reninangiotensin system, is implicated in the pathogenesis of Alzheimer's disease (AD). However, it remains unknown whether activation or blockade of the angiotensin II type 1 receptor (AT1R) has an impact on the secretion of amyloid-beta (A beta), the key molecule in the pathogenesis of AD. In this study, the cell models cultured primary hippocampal neurons and human embryonic kidney 293 cells, were transfected with AT1R and amyloid precursor protein/presenilin-1 (PS1). The effects of activation/blockade of the AT1R on A beta secretion, PS1 level and beta-/gamma-secretase activity were investigated in different cells. When AT1R was stimulated with Ang II at concentrations from 10 nM to 1000 nM, only a tendency toward increased A beta secretion and beta-/gamma-secretase activity was noticed in cultured primary hippocampal neurons. However, no significant change in soluble A beta(40) or A beta(42), the level of PS1, or secretase activity was found in the cells. Similarly, when the AT1R was blocked by losartan, no significant alteration of A beta secretion, PS1 levels or secretase activity was detected. In conclusion, this in vitro study demonstrates that Ang II does not directly affect A beta secretion or secretase activity via activation of AT1R. This study is significantly meaningful for exploring the pharmacologic mechanisms of angiotensin II receptor blockers in AD. (C) 2011 Elsevier Ireland Ltd. All rights reserved.