P2-364: Improvement of cognitive decline and cerebrovascular dysfunction in a mouse model of Alzheimer's disease by the angiotensin receptor blocker, olmesartan

Abstract

Recent epidemiological studies suggest that some kind of antihypertensive drugs may reduce the incidence of Alzheimer's disease, but their mechanisms are not fully investigated. In the present study, we examined the effect of angiotensin receptor blocker (olmesartan) on cognitive function in a mouse model of Alzheimer's disease. Eight-week-old male ddY mice were administered angitensin receptor blocker (olmesartan; 0.5, 1.0, 3.0, 6.0mg/kg/day) or hydralazine (30mg/kg/day) in drinking water for 4 weeks. After 4 weeks of pre-treatment, beta-amyloid peptide (Aβ) was injected into cerebroventricle bilaterally. 6 days after Aβ injection, we examined cognitive function of the model mice using a battery of learning and memory behavior test (Morris water maze) and hippocampal synaptic plasticity with a field recording technique. We also examined cerebrovascular reactivity using a cerebral blood flow monitoring system with laser-Doppler flowmetry and analyzed oxidative stress in the brain vessels biochemically and immunohistochemically. Furthermore, we assessed these effects in an Alzheimer disease model of transgenic mouse. Blood pressure of olmesartan treated mice was decreased significantly and dose-dependently after 4 weeks administration. Low-dose of olmesartan (0.5∼1.0mg/kg/day), which did not induce excessive hypotension, significantly reduced Aβ-mediated cognitive deficit, but not in higher doses (3.0∼6.0mg/kg/day). Hydralazine (30mg/kg/day), which has an equivalent blood-lowering effect to low-dose olmesartan, did not exert such a favorable effect on cognitive function. Synaptic plasticity of hippocampal CA1 area was also significantly improved in low-dose olmesartan (1.0mg/kg/day) treated group. Olmesartan improved Aβ-mediated cerebrovascular dysfunction such as impairment in autoregulation of cerebral blood flow and functional hyperemia induced by whisker stimulation. Low-dose of olmesartan reduced cognitive deficit in a mouse model of Alzheimer's disease associated with an improvement of cerebrovascular reactivity. This preclinical evidence supports the idea that angiotensin receptor blocker would contribute to alleviation of Aβ mediated cognitive dysfunction and the potential use of this class of drug in the treatment and prevention of Alzheimer's disease.