title: Differential effects of angiotensin II receptor blockers on Aβ generation.
abstract: Angiotensin II receptor blockers (ARBs) are widely prescribed for the medication of systemic hypertension and congestive heart failure. It has been reported that ARBs can reduce the risk for the onset of Alzheimer's disease (AD) and have beneficial effects on dementia. Neurotoxic amyloid β-protein (Aβ) is believed to play a causative role in the development of AD. However, whether ARBs regulate Aβ generation remains largely unknown. Here, we studied the effect of ARBs on Aβ generation and found that telmisartan significantly increased Aβ40 and Aβ42 generation, but decreased the Aβ42/Aβ40 ratio. However, losartan, valsartan and candesartan did not increase Aβ generation, while olmesartan significantly increased Aβ42 generation. We also found that telmisartan increased the Aβ generation through angiotensin type 1a receptor (AT1a) and the receptor-related phosphotidylinositide 3-kinases (PI3K) pathway. Our findings revealed the different effects of ARBs on Aβ generation and provide new evidence for the relationship between antihypertensive treatment and AD pathogenesis.
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Junjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tanabe
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan. Electronic address: kunzou@iwate-med.ac.jp.
authors.forename: Kun
authors.initials: K
authors.lastname: Zou
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan. Electronic address: hkomano@iwate-med.ac.jp.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Komano
mesh_terms: D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects*; D000818:Animals; D001562:Benzimidazoles / Q000009:adverse effects; D001565:Benzoates / Q000009:adverse effects; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000009:adverse effects; D019808:Losartan / Q000009:adverse effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000077333:Telmisartan; D013777:Tetrazoles / Q000009:adverse effects; D014633:Valine / Q000009:adverse effects / Q000031:analogs & derivatives; D000068756:Valsartan
chemical_list: D016229:Amyloid beta-Peptides; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D007093:Imidazoles; D019808:Losartan; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D044140:Receptor, Angiotensin, Type 1; D000077333:Telmisartan; D013777:Tetrazoles; D014633:Valine; D000068756:Valsartan; C544066:Agtr1a protein, mouse; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C437965:olmesartan; C081643:candesartan
keywords: Alzheimer's disease; Amyloid β-protein; Angiotensin II receptor blockers