Biliverdin reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease
Biliverdin reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease
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DOI：
10.1111/j.1471-4159.2011.07538.x
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发表时间：
2012-01-01
影响因子：
4.7
通讯作者：
Butterfield, D. Allan
中科院分区：
文献类型：
--
作者：
Barone, Eugenio;Mancuso, Cesare;Butterfield, D. Allan
胆绿素还原酶- a （BVR-A）是一种参与细胞应激反应的多效酶。它不仅将胆红素- ix α转化为抗氧化剂胆红素- ix α，而且通过其丝氨酸/苏氨酸/酪氨酸激酶活性能够调节细胞信号网络。BVR-As参与神经退行性疾病，如阿尔茨海默病（AD）和遗忘性轻度认知障碍。他汀类药物被建议用于降低阿尔茨海默病的风险。在这项研究中，我们评估了阿托伐他汀治疗（80 mg/天，14.5个月）对老年小猎犬阿尔茨海默病临床前模型顶叶皮层、小脑和肝脏中BVR-A的影响。我们发现阿托伐他汀仅在顶叶皮层显著增加BVR-A蛋白水平、磷酸化和活性。此外，我们发现BVR-A与氧化应激指数以及辨别学习错误得分呈显著负相关。此外，BVR-A的上调和翻译后修饰与大脑中β -分泌酶蛋白水平显著相关，表明BVR-A可能在a- β的形成中发挥作用。
Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but through its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. BVR-As involvement in neurodegenerative disorders such as Alzheimer disease (AD) and amnestic mild cognitive impairment was previously described. Statins have been proposed to reduce risk of AD. In this study we evaluated the effect of atorvastatin treatment (80 mg/day for 14.5 months) on BVR-A in the parietal cortex, cerebellum and liver of a well characterized pre-clinical model of AD, the aged beagle. We found that atorvastatin significantly increased BVR-A protein levels, phosphorylation and activity only in parietal cortex. Additionally, we found significant negative correlations between BVR-A and oxidative stress indices, as well as discrimination learning error scores. Furthermore, BVR-A up-regulation and post-translational modifications significantly correlated with beta-secretase protein levels in the brain, suggesting a possible role for BVR-A in A beta formation.