Hattori Yorito, Maki Takakuni, Saito Satoshi, Yamamoto Yumi, Nagatsuka Kazuyuki, Ihara Masafumi
Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan.
J Alzheimers Dis. 2016 Apr 12;52(3):1037-45. doi: 10.3233/JAD-160013.
Accumulation of amyloid-β peptide (Aβ) in the brain is one of the most important features of Alzheimer's dementia (AD). Cerebral amyloid angiopathy (CAA) is characterized by Aβ accumulation in the walls of cerebral arteries and capillaries, and is present in over 90% of patients with AD. Several novel agents for AD/CAA developed around the amyloid hypothesis have shown positive signs in animal studies but have failed in clinical trials due to adverse events and/or lack of efficiency. As CAA is presumably caused by a failure in Aβ clearance, drugs that promote Aβ clearance may hold promise in the treatment of CAA and possibly AD. With this in mind, cilostazol, an anti-platelet drug with vasodilating action, has been found to promote Aβ clearance along perivascular drainage pathway, reduce Aβ accumulation in the brain, and restore memory impairment in Tg-SwDI mice, an animal model of CAA. We therefore tested whether the most common anti-platelet agent, aspirin, also reduced Aβ and rescued cognitive impairment in Tg-SwDI mice, and also whether aspirin affected hemorrhagic complications that can occur in Tg-SwDI mice. Mice aged 4 months were assigned into vehicle-treated and low-dose aspirin-treated groups. Low-dose aspirin for 8 months did not increase hemorrhagic lesions, nor increase resting cerebral blood flow or cerebral vascular reserve in response to hypercapnia or acetylcholine. Subsequently, aspirin did not restore cognitive dysfunction. These results suggest that low-dose aspirin does not have a direct influence on cerebrovascular Aβ metabolism nor aggravate hemorrhagic complications in CAA.
β-淀粉样肽（Aβ）在大脑中的积累是阿尔茨海默病性痴呆（AD）最重要的特征之一。脑淀粉样血管病（CAA）的特征是Aβ在脑动脉和毛细血管壁中积累，超过90%的AD患者存在这种情况。围绕淀粉样蛋白假说开发的几种用于AD/CAA的新型药物在动物研究中显示出阳性迹象，但由于不良事件和/或缺乏疗效，在临床试验中失败了。由于CAA可能是由Aβ清除失败引起的，促进Aβ清除的药物可能在治疗CAA以及可能的AD方面具有前景。考虑到这一点，已发现具有血管舒张作用的抗血小板药物西洛他唑可促进Aβ沿血管周围引流途径清除，减少大脑中Aβ的积累，并恢复CAA动物模型Tg-SwDI小鼠的记忆障碍。因此，我们测试了最常用的抗血小板药物阿司匹林是否也能减少Tg-SwDI小鼠的Aβ并挽救其认知障碍，以及阿司匹林是否会影响Tg-SwDI小鼠可能出现的出血并发症。将4个月大的小鼠分为溶剂处理组和低剂量阿司匹林处理组。低剂量阿司匹林处理8个月既没有增加出血性病变，也没有增加静息脑血流量或对高碳酸血症或乙酰胆碱的脑血管储备。随后，阿司匹林未能恢复认知功能障碍。这些结果表明，低剂量阿司匹林对脑血管Aβ代谢没有直接影响，也不会加重CAA的出血并发症。
