Angiotensin receptor blocker prevented beta-amyloid-induced cognitive impairment associated with recovery of neurovascular coupling.
Recent studies suggest that vascular risk factors play a considerable role in the development of Alzheimer disease. Furthermore, the use of antihypertensive drugs has been suggested to reduce the incidence of dementia, including Alzheimer disease. In this study, we examined the effects of an angiotensin receptor blocker, olmesartan, on beta-amyloid-induced cerebrovascular dysfunction and cognitive impairment. Oral administration of a low dose of olmesartan attenuated cerebrovascular dysfunction in young Alzheimer disease-model transgenic mice (APP23 mouse), without a reduction in the brain beta-amyloid level. Moreover, treatment of APP23 mice with olmesartan decreased oxidative stress in brain microvessels. Using an acute mouse model induced by ICV administration of beta-amyloid 1-40, we assessed the effect of oral administration of olmesartan on spatial learning evaluated with the Morris water maze. Olmesartan significantly improved cognitive function independent of its blood pressure-lowering effect, whereas there was no improvement by other types of antihypertensive drugs (hydralazine and nifedipine). We found that pretreatment with a low dose of olmesartan completely prevented beta-amyloid-induced vascular dysregulation and partially attenuated the impairment of hippocampal synaptic plasticity. These findings suggest the possibility that amelioration of cerebrovascular dysfunction with an angiotensin receptor blocker could be a novel therapeutic strategy for the early stage of Alzheimer disease.
Takeda
Shuko
S
Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Sato
Naoyuki
N
Takeuchi
Daisuke
D
Kurinami
Hitomi
H
Shinohara
Mitsuru
M
Niisato
Kazue
K
Kano
Masanobu
M
Ogihara
Toshio
T
Rakugi
Hiromi
H
Morishita
Ryuichi
R
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism* / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D013777:Tetrazoles; C078592:amyloid beta-protein (1-40); C437965:olmesartan