Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 405360230, USA.
J Alzheimers Dis. 2010;22(1):135-50. doi: 10.3233/JAD-2010-100639.
Human studies suggest either a protective role or no benefit of statins against the development of Alzheimer's disease (AD). We tested the hypothesis that statin-mediated cholesterol reduction in aged dogs, which have cognitive impairments and amyloid-β (Aβ) pathology, would improve cognition and reduce neuropathology. In a study of 12 animals, we treated dogs with 80 mg/day of atorvastatin for 14.5 months. We did not observe improvements in discrimination learning; however, there were transient impairments in reversal learning, suggesting frontal dysfunction. Spatial memory function did not change with treatment. Peripheral levels of cholesterol, LDLs, triglycerides, and HDL were significantly reduced in treated dogs. Aβ in cerebrospinal fluid and brain remained unaffected. However, β-secretase-1 (BACE1) protein levels and activity decreased and correlated with reduced brain cholesterol. Finally, lipidomic analysis revealed a significant decrease in the ratio of omega-6 to omega-3 essential fatty in temporal cortex of treated aged dogs. Aged beagles are a unique model that may provide novel insights and translational data that can predict outcomes of statin use in human clinical trials. Treatment with atorvastatin may be beneficial for brain aging by reducing BACE1 protein and omega6:omega3 ratio, however, the potential adverse cognitive outcomes reported here should be more carefully explored given their relevance to human clinical outcomes.
人类研究表明，他汀类药物对阿尔茨海默病（AD）的发展既没有保护作用，也没有益处。我们检验了这样一个假设，即在认知功能障碍和淀粉样蛋白-β（Aβ）病理学的老年犬中，他汀类药物降低胆固醇会改善认知并减少神经病理学。在一项针对 12 只动物的研究中，我们用 80 毫克/天的阿托伐他汀治疗狗 14.5 个月。我们没有观察到辨别学习的改善；然而，在反转学习中存在短暂的损伤，这表明额叶功能障碍。治疗并未改变空间记忆功能。治疗犬的外周胆固醇、LDL、甘油三酯和 HDL 水平显著降低。脑脊液和大脑中的 Aβ 仍然不受影响。然而，β-分泌酶-1（BACE1）蛋白水平和活性降低，与大脑胆固醇减少相关。最后，脂质组学分析显示，治疗的老年犬颞叶皮质中ω-6 到 ω-3 必需脂肪酸的比例显著降低。老年比格犬是一种独特的模型，它可能提供新的见解和转化数据，这些数据可以预测他汀类药物在人类临床试验中的应用结果。阿托伐他汀治疗可能通过降低 BACE1 蛋白和 ω6:ω3 比值对大脑衰老有益，然而，鉴于其与人类临床结果的相关性，这里报告的潜在认知不良后果应更仔细地探索。
