Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice
Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice
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DOI：
10.1016/j.expneurol.2006.01.018
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发表时间：
2006-06-01
影响因子：
5.3
通讯作者：
Haynatzki, Gleb R.
中科院分区：
文献类型：
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作者：
Pedersen, Ward A.;McMillan, Pamela J.;Haynatzki, Gleb R.
噻唑烷二酮类药物，如罗格列酮，增加外周胰岛素敏感性，它们被建议用于治疗阿尔茨海默病。然而，罗格列酮在阿尔茨海默病中潜在有益作用的机制尚不清楚。在之前的研究中，我们观察到Tg2576老年痴呆症小鼠随着年龄的增长出现外周胰岛素抵抗，并且在禁食过夜时血清皮质酮水平远高于野生型小鼠。我们进一步表明，这两种缺陷都可以通过罗格列酮改善。在行为学测试中，研究人员发现服用罗格列酮的Tg2576小鼠表现出更好的空间学习和记忆能力，且血清皮质酮水平低于未服用罗格列酮的Tg2576小鼠。未治疗的Tg2576小鼠给予阻断糖皮质激素产生的药物美替拉酮后，其空间学习记忆能力和血清皮质酮水平与罗格列酮治疗小鼠相似。我们在这里进一步报道，罗格列酮减轻了Tg2576小鼠大脑中胰岛素降解酶（IDE） mRNA和活性的降低，并降低了淀粉样蛋白β肽（A β）42的水平，而不影响淀粉样蛋白沉积。这些结果表明，罗格列酮可以减轻Tg2576小鼠的学习和记忆缺陷，并提示该药物对小鼠学习和记忆、大脑IDE水平和大脑A β 42水平的影响可能是由于其糖皮质激素的降低作用。(c) 2006爱思唯尔公司版权所有。
The thiazolidinediones, such as rosiglitazone, increase peripheral insulin sensitivity and their use is proposed for the treatment of Alzheimer's disease. However, the mechanisms underlying the potential beneficial effects of rosiglitazone in Alzheimer's disease remain unclear. In previous studies, we observed that Tg2576 Alzheimer mice develop peripheral insulin resistance with age and have much higher serum corticosterone levels than wild-type mice when fasted overnight. We further showed that both of these defects can be ameliorated by rosiglitazone administration. Here, we report that during behavioral testing which involves repetitive overnight fasting, Tg2576 mice administered rosiglitazone exhibited better spatial learning and memory abilities and had lower serum corticosterone levels than untreated Tg2576 mice. When untreated Tg2576 mice were administered metyrapone, a drug that blocks glucocorticoid production, their spatial learning and memory abilities and serum corticosterone levels were similar to those of rosiglitazone-treated mice. We further report here that rosiglitazone attenuated reductions in insulin-degrading enzyme (IDE) mRNA and activity, and reduced amyloid beta-peptide (A beta)42 levels without affecting amyloid deposition, in the brains of Tg2576 mice. These results demonstrate that rosiglitazone attenuates learning and memory deficits in Tg2576 mice and suggest that the effects of the drug on learning and memory, brain IDE levels, and brain A beta 42 levels in the mice may be due to its glucocorticoid-lowering actions. (c) 2006 Elsevier Inc. All rights reserved.