Abstract T MP72: Mild Cerebral Ischemia Combined With Cerebral Amyloid Angiopathy Significantly Deteriorated Cognitive Impairment via Angiotensin At1 Receptor in a Mouse Model of Alzheimer’S Disease

Abstract

Introduction: Ischemic stroke is suggested to be potentially associated with cognitive impairment in Alzheimer’s disease. Recent clinical data suggest that treatment with angiotensin receptor blocker (ARB) is associated with less incidence of Alzheimer’s disease than other classes of antihypertensive drugs. However, it is unknown whether cerebral ischemia can indeed trigger cognitive decline in Alzheimer’s disease and whether ARB can exert beneficial effect on ischemia-induced cognitive decline. Hypothesis: We hypothesized that mild cerebral ischemia deteriorates cognitive impairment in Alzheimer’s disease, through angiotensin II. Methods: We used 5XFAD mouse, a model of Alzheimer’s disease with vascular and cerebral amyloid-β(Aβ) deposition. Mild transient cerebral ischemia of mice was induced by bilateral common carotid artery occlusion (BCCAO) for 15 minutes. The post-treatment with olmesartan, an ARB, or vehicle was started at 24 hours after BCCAO, and was performed for 5 weeks. To evaluate cognitive impairment, we performed Morris Water maze test (reference-/working-memory), Passive avoidance test (learning memory), and Open field test (general locomotor activity and anxiety). Results and Conclusions: There were no significant differences in cognitive function between 5XFAD and wild type mice without BCCAO. BCCAO in 5XFAD caused greater escape latency (p<0.05) on Water maze test and greater migration distance (p<0.05) on Open field test than that in wild type mice, indicating that mild cerebral ischemia combined with Aβ deposition enhanced cognitive decline. Post-treatment with olmesartan significantly reduced escape latency (p<0.01) and number of crossing platform (p<0.01) on Water maze test, retention trial latency (p<0.05) on Passive avoidance test, and retention time of outer zone (p<0.01) on Open field test in 5XFAD subjected to BCCAO, indicating the improvement of working memory, learning memory and anxiety by olmesartan. Thus, the deterioration of cognitive impairment by BCCAO in 5XFAD was mediated by AT1 receptor. In conclusion, we first demonstrated that mild cerebral ischemia combined with cerebral amyloid angiopathy markedly deteriorates cognitive impairment, through AT1 receptor.