Department of Pharmacology and Toxicology, Georgia Health Sciences University, Augusta, GA 30912, USA.
Free Radic Biol Med. 2012 Aug 1;53(3):577-88. doi: 10.1016/j.freeradbiomed.2012.04.010. Epub 2012 Apr 21.
Amyloid β peptides (Aβ) have been implicated in the pathogenesis of age-related macular degeneration (ARMD) and glaucoma. In this study, retinas of mice overexpressing Aβ (Tg) were compared to those of wild-type mice (Wt) and analyzed for oxidative stress parameters. We observed a progressive decrease in all retinal cell layers, which was significantly greater in Tg mice at 14 months and culminated in loss of the outer retina at 18 months of age. We also observed higher levels of reactive oxygen species, glial fibrillary acidic protein, and hydroperoxide in Tg versus Wt mice (14 months). These effects were associated with phosphorylation/activation of the apoptosis signal kinase 1 and the p38 mitogen-activated kinase. Western blotting analysis revealed progressive increases in the levels of thioredoxin 1 and thioredoxin inhibitory protein in Tg compared to Wt mice. No changes were observed in the levels of thioredoxin reductase 1 (TrxR1); however, measurements of TrxR1 activity showed a 42.7±8% reduction in Tg mice versus Wt at 14 months of age. Our data suggest that Aβ-mediated retinal neurotoxicity involves impairment of the thioredoxin system and enhanced oxidative stress, potentially implicating this mechanism in the pathogenesis of ARMD and glaucoma.
淀粉样 β 肽 (Aβ) 与年龄相关性黄斑变性 (ARMD) 和青光眼的发病机制有关。在这项研究中，比较了过表达 Aβ 的小鼠 (Tg) 和野生型小鼠 (Wt) 的视网膜，并分析了氧化应激参数。我们观察到所有视网膜细胞层逐渐减少，Tg 小鼠在 14 个月时减少更为明显，到 18 个月时外视网膜丧失。我们还观察到 Tg 小鼠中活性氧、神经胶质纤维酸性蛋白和过氧化物的水平高于 Wt 小鼠 (14 个月)。这些影响与凋亡信号激酶 1 和 p38 丝裂原激活蛋白激酶的磷酸化/激活有关。Western blot 分析显示，与 Wt 小鼠相比，Tg 小鼠中硫氧还蛋白 1 和硫氧还蛋白抑制蛋白的水平逐渐增加。TrxR1 水平没有变化；然而，在 14 个月时，Tg 小鼠的 TrxR1 活性测量显示比 Wt 小鼠降低了 42.7±8%。我们的数据表明，Aβ 介导的视网膜神经毒性涉及硫氧还蛋白系统的损伤和氧化应激的增强，这可能表明该机制参与了 ARMD 和青光眼的发病机制。
