Abstract

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.