Department of Clinical Medicine, Southeast University, Nanjing, China.
J Neurochem. 2012 Jul;122(2):456-69. doi: 10.1111/j.1471-4159.2012.07783.x. Epub 2012 Jun 6.
Oxidative stress and neuroinflammation play important roles in Alzheimer's disease (AD). ABCG2 is a transporter protein expressed in the brain and involved in GSH transport. To study the roles of Abcg2 in oxidative stress and AD, we cross-bred Tg-SwDI and Abcg2-KO mice and generated Tg-SwDI/Abcg2-KO (double-tg) mice. Brain tissues from double-tg, Tg-SwDI, wild-type, and Abcg2-KO mice at various ages were analyzed. Aβ40 and Aβ42 were detected in Tg-SwDI and double-tg mice. Total brain GSH was decreased and levels of lipid/DNA oxidation were increased in 3-month double-tg compared to Tg-SwDI mice. Low brain GSH was still detected in 9-month double-tg mice. Increased HMOX-1 and MCP-5 expression was observed in 9-month double-tg mice but not in Tg-SwDI mice compared to WT and Abcg2-KO mice. Increased HMOX-1 and decreased ICAM-1 expression were observed in 12-month double-tg mice compared to Tg-SwDI mice. The levels of Nrf-2 expression and activity were decreased in 6-month double-tg mice. Behavioral tests show impaired cognitive/memory performance of 9-month double-tg compared to Tg-SwDI mice as well as WT and Abcg2-KO mice. These results suggest that Abcg2 deficiency increases oxidative stress and alters inflammatory response in the brain and exacerbates cognitive/memory deficit in double-tg mice at different developmental stages.
氧化应激和神经炎症在阿尔茨海默病（AD）中发挥重要作用。ABCG2 是一种在大脑中表达的转运蛋白，参与 GSH 转运。为了研究 Abcg2 在氧化应激和 AD 中的作用，我们将 Tg-SwDI 和 Abcg2-KO 小鼠进行杂交，并产生了 Tg-SwDI/Abcg2-KO（双转基因）小鼠。分析了不同年龄的双转基因、Tg-SwDI、野生型和 Abcg2-KO 小鼠的脑组织。在 Tg-SwDI 和双转基因小鼠中检测到 Aβ40 和 Aβ42。与 Tg-SwDI 小鼠相比，3 月龄双转基因小鼠的总脑 GSH 减少，脂质/DNA 氧化水平升高。在 9 月龄双转基因小鼠中仍检测到低脑 GSH。与 WT 和 Abcg2-KO 小鼠相比，9 月龄双转基因小鼠中观察到 HMOX-1 和 MCP-5 表达增加，但 Tg-SwDI 小鼠中没有。与 Tg-SwDI 小鼠相比，12 月龄双转基因小鼠中观察到 HMOX-1 增加和 ICAM-1 表达减少。与 6 月龄双转基因小鼠相比，Nrf-2 表达和活性降低。行为测试显示，与 Tg-SwDI 小鼠以及 WT 和 Abcg2-KO 小鼠相比，9 月龄双转基因小鼠的认知/记忆能力受损。这些结果表明，Abcg2 缺乏增加了大脑中的氧化应激和改变了炎症反应，并在不同发育阶段的双转基因小鼠中加剧了认知/记忆缺陷。
