title: Angiotensin II does not directly affect Aβ secretion or β-/γ-secretase activity via activation of angiotensin II type 1 receptor.
abstract: Recent studies suggest that brain angiotensin II (Ang II), the major effector molecule of the renin-angiotensin 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-β (Aβ), 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 Aβ secretion, PS1 level and β-/γ-secretase activity were investigated in different cells. When AT1R was stimulated with Ang II at concentrations from 10nM to 1000nM, only a tendency toward increased Aβ secretion and β-/γ-secretase activity was noticed in cultured primary hippocampal neurons. However, no significant change in soluble Aβ(40) or Aβ(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 Aβ secretion, PS1 levels or secretase activity was detected. In conclusion, this in vitro study demonstrates that Ang II does not directly affect Aβ 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.
authors.affiliation: Department of Neurology, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
authors.forename: Bian-Rong
authors.initials: BR
authors.lastname: Wang
authors.forename: Jian-Quan
authors.initials: JQ
authors.lastname: Shi
authors.forename: Ying-Dong
authors.initials: YD
authors.lastname: Zhang
authors.forename: Dong-Lin
authors.initials: DL
authors.lastname: Zhu
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Shi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists* / Q000235:genetics; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D047228:Angiotensin II Type 1 Receptor Blockers; D010446:Peptide Fragments; D053764:Presenilin-1; D044140:Receptor, Angiotensin, Type 1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D000804:Angiotensin II; D053829:Amyloid Precursor Protein Secretases; D019808:Losartan