Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
Institute of Cell Biology, University of Bern, Switzerland.
J Alzheimers Dis. 2016;51(4):1183-95. doi: 10.3233/JAD-150868.
The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-β protein precursor (AβPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-β (Aβ) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aβ plaque burden, a tendency not significant when Aβ1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients.
血管紧张素转换酶抑制剂 (ACEi) 和血管紧张素 II (AngII) 受体阻滞剂 (ARB) 的联合使用，可结合血管紧张素 1 型受体 (AT1R)，其对阿尔茨海默病 (AD) 的保护作用可能优于单一药物治疗。我们检测了非穿透血脑屏障的 ACEi 依那普利（3mg/kg/天）单独或与穿透血脑屏障的 ARB 洛沙坦（10mg/kg/天）联合治疗 3 个月，对表达人淀粉样前体蛋白突变体（此后称为 APP 小鼠）的老年（约 15 个月）转基因小鼠的治疗效果。我们研究了脑血管功能、氧化应激标志物（超氧化物歧化酶 SOD1、SOD2 和 NADPH 氧化酶亚单位 p67phox）、淀粉样蛋白-β（Aβ）病理学、星形胶质细胞增生、胆碱能神经支配、AT1R 和血管紧张素 IV 受体（AT4R）水平以及认知功能。两种治疗方法都能使脑血管反应性和 p67phox 蛋白水平正常化，但不能降低脑血管 SOD1 水平。联合治疗使脑血管 SOD2 水平正常化，显著减弱星形胶质细胞增生，但不能降低增加的脑血管 AT1R 水平。然而，联合治疗增强了硫黄素-S 标记的 Aβ斑块负担，当考虑 Aβ1-42 斑块负荷时，这种趋势并不显著。两种治疗方法均不能改善认知缺陷、皮质 AT4R 或胆碱能神经支配。我们的结论是，两种治疗方法通过抑制 AngII 诱导的氧化应激级联反应使脑血管功能正常化，联合治疗对星形胶质细胞增生的积极作用可能归因于洛沙坦进入脑实质的能力。然而，依那普利没有增强，甚至可能抑制，洛沙坦报告的认知益处，在选择 AD 患者最合适的降压治疗时应谨慎。
