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 cerebral ischemia deteriorates cognitive impairment in Alzheimer’s disease, through angiotensin II.
Methods and results: We used 5XFAD mouse, a model of Alzheimer’s disease with vascular and cerebral amyloid-β(Aβ) deposition. Transient cerebral ischemia of mice was induced by bilateral common carotid artery occlusion (BCCAO) for 17 minutes. The post-treatment with olmesartan, an ARB, or vehicle was started at 24 hours after BCCAO, and was performed for 5 weeks. Mice were divided into 5 groups: (1) wild type, (2) wild type with BCCAO, (3) 5XFAD, (4) 5XFAD with BCCAO, (5) 5XFAD with BCCAO and olmesartan administration, to evaluate cognitive impairment. BCCAO in 5XFAD caused greater escape latency (p<0.01) on Water maze test (reference-/working-memory) and greater migration distance (p<0.05) on Open field test than that in wild type, indicating that cerebral ischemia combined with Aβ deposition enhanced cognitive decline. Post-treatment with olmesartan significantly reduced escape latency (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. BCCAO significantly deteriorated cognitive impairment, and this protection against BCCAO by olmesartan was associated with the protection of neuron in hippocampus and the suppression of blood-brain barrier disruption. Furthermore, olmesartan significantly attenuated brain oxidative stress, and NADPH oxidase subunits P67 in 5XFAD.
Conclusion: We first demonstrated that cerebral ischemia combined with amyloid angiopathy markedly deteriorates cognitive impairment in 5XFAD mouse, through AT1 receptor.