Staurenghi Erica, Testa Gabriella, Leoni Valerio, Cecci Rebecca, Floro Lucrezia, Giannelli Serena, Barone Eugenio, Perluigi Marzia, Leonarduzzi Gabriella, Sottero Barbara, Gamba Paola
Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, 10043 Orbassano, Italy.
Laboratory of Clinical Pathology, Hospital Pio XI of Desio, ASST-Brianza and Department of Medicine and Surgery, University of Milano-Bicocca, 20832 Desio, Italy.
Antioxidants (Basel). 2024 Apr 3;13(4):435. doi: 10.3390/antiox13040435.
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.
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）的一种基因决定形式。维持脑胆固醇稳态对脑功能和发育至关重要，其失调与AD神经炎症和氧化损伤相关。脑胆固醇失衡也可能发生在DS中，与早熟的AD样神经退行性变同时出现。在这项初步研究中，我们分析了DS的Ts2Cje（Ts2）小鼠模型大脑中参与胆固醇代谢的关键酶编码基因的表达以及胆固醇及其主要前体和代谢产物（即氧化甾醇）的水平。结果显示，与正常小鼠相比，Ts2小鼠中编码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转录下调，后者最初被认为是AD的一个指标，总胆固醇水平随之降低。此外，Ts2小鼠大脑中负责脑胆固醇氧化的酶编码基因的表达以及由此产生的氧化甾醇的量发生了改变，胆固醇自氧化产物的水平升高，表明脑氧化应激加剧。我们还观察到Ts2小鼠的炎症反应增强，这通过编码α-干扰素和白细胞介素-6的基因转录上调得到强调，这两种细胞因子在AD患者大脑中的合成增加。总体而言，这些结果表明DS和AD大脑存在共同的胆固醇循环紊乱和氧化甾醇水平改变，这可能导致两种疾病中涉及的氧化和炎症事件。
