PDF(Pubmed)
Abstract：
Down syndrome (DS) is a complex chromosomal disorder considered as a genetically determined form of Alzheimer\'s disease (AD). Maintenance of brain cholesterol homeostasis is essential for brain functioning and development, and its dysregulation is associated with AD neuroinflammation and oxidative damage. Brain cholesterol imbalances also likely occur in DS, concurring with the precocious AD-like neurodegeneration. In this pilot study, we analyzed, in the brain of the Ts2Cje (Ts2) mouse model of DS, the expression of genes encoding key enzymes involved in cholesterol metabolism and of the levels of cholesterol and its main precursors and products of its metabolism (i.e., oxysterols). The results showed, in Ts2 mice compared to euploid mice, the downregulation of the transcription of the genes encoding the enzymes 3-hydroxy-3-methylglutaryl-CoA reductase and 24-dehydrocholesterol reductase, the latter originally recognized as an indicator of AD, and the consequent reduction in total cholesterol levels. Moreover, the expression of genes encoding enzymes responsible for brain cholesterol oxidation and the amounts of the resulting oxysterols were modified in Ts2 mouse brains, and the levels of cholesterol autoxidation products were increased, suggesting an exacerbation of cerebral oxidative stress. We also observed an enhanced inflammatory response in Ts2 mice, underlined by the upregulation of the transcription of the genes encoding for α-interferon and interleukin-6, two cytokines whose synthesis is increased in the brains of AD patients. Overall, these results suggest that DS and AD brains share cholesterol cycle derangements and altered oxysterol levels, which may contribute to the oxidative and inflammatory events involved in both diseases.
摘要：
唐氏综合征（DS）是一种复杂的染色体疾病，被认为是阿尔茨海默病（AD）的遗传决定形式。维持大脑胆固醇稳态对于大脑功能和发育至关重要，其失调与AD神经炎症和氧化损伤有关。大脑胆固醇失衡也可能发生在DS中，符合性早熟的AD样神经变性。在这项试点研究中，我们分析了,在DS的Ts2Cje（Ts2）小鼠模型的大脑中，编码参与胆固醇代谢的关键酶的基因的表达以及胆固醇及其代谢的主要前体和产物的水平(即，氧固醇）。结果显示,在Ts2小鼠中与整倍体小鼠相比，下调编码酶3-羟基-3-甲基戊二酰辅酶A还原酶和24-脱氢胆固醇还原酶的基因的转录，后者最初被认为是AD的指标，以及随之而来的总胆固醇水平的降低。此外，在Ts2小鼠大脑中，编码负责脑胆固醇氧化的酶的基因表达和所产生的氧固醇的量被改变，胆固醇自动氧化产品的水平增加，提示大脑氧化应激加剧.我们还观察到Ts2小鼠的炎症反应增强，编码α-干扰素和白介素-6的基因转录上调，这两种细胞因子在AD患者的大脑中合成增加。总的来说,这些结果表明，DS和AD大脑共享胆固醇周期紊乱和氧固醇水平改变，这可能有助于这两种疾病的氧化和炎症事件。
