Alzheimer’s disease (AD) is a progressive neurodegenerative disorder typified by several neuropathological features including amyloid-beta (Aβ) plaque and neurofibrillary tangles (NFTs). Cholesterol retention and oxidative stress (OS) are the major contributors of elevated β- and γ-secretase activities, leading to excessive Aβ deposition, signifying the importance of altered cholesterol homeostasis and OS in the progression of Aβ-mediated neurodegeneration and cognitive deficit. However, the effect of Aβ on cholesterol metabolism is lesser-known. In this study, we evaluated the effect of quinovic acid (QA; 50 mg/kg body weight, i.p.) against the intracerebroventricular (i.c.v.) injection of Aβ (1-42)-induced cholesterol dyshomeostasis, oxidative stress, and neurodegeneration in the cortex and hippocampal brain regions of wild-type male C57BL/6J mice. Our results indicated that Aβ (1-42)-treated mice have increased Aβ oligomer formation along with increased β-secretase expression. The enhanced amyloidogenic pathway in Aβ (1-42)-treated mice intensified brain cholesterol accumulation due to increased expressions of p53 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) enzyme. Importantly, we further confirmed the p53-mediated HMGCR axis activation by using pifithrin-α (PFT) in SH-SY5Y cells. Furthermore, the augmented brain cholesterol levels were also associated with increased OS. However, the QA administration to Aβ (1-42)-injected mice significantly ameliorated the Aβ burden, p53 expression, and cholesterol accumulation by deterring the oxidative stress through upregulating the Nrf2/HO-1 pathway. Moreover, the QA downregulated gliosis, neuroinflammatory mediators (p-NF-κB and IL-1β), and the expression of mitochondrial apoptotic markers (Bax, cleaved caspase-3, and cytochrome c). QA treatment also reversed the deregulated synaptic markers (PSD-95 and synaptophysin) and improved spatial learning and memory behaviors in the Aβ-treated mouse brains. These results suggest that Aβ (1-42) induces its acute detrimental effects on cognitive functions probably by increasing brain cholesterol levels through a possible activation of the p53/HMGCR axis. However, QA treatment reduces the cholesterol-induced oxidative stress, neuroinflammation, and neurodegeneration, leading to the restoration of cognitive deficit after Aβ (1-42) i.c.v. injection in mice.

中文翻译：

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奎诺维奇酸可阻止胆固醇淀粉样代谢异常，氧化应激和淀粉样β诱导的小鼠模型中的神经变性。

阿尔茨海默氏病（AD）是由若干神经病理学特征，包括淀粉样蛋白-β（A为代表的进行性神经变性病症β）斑块和神经原纤维缠结（NFTs的）。胆固醇保留和氧化应激（OS）是升高的主要贡献者β -和γ分泌酶的活动，从而导致过度的甲β沉积，表示在A的进展改变的胆固醇体内平衡和OS的重要性β介导的神经变性和认知缺陷。然而，A的影响β关于胆固醇的代谢鲜为人知。在这项研究中，我们评价quinovic酸的作用（QA; 50毫克/公斤体重，腹膜内）对脑室内（ICV）注射A的β（1-42）诱导的胆固醇dyshomeostasis，氧化应激，和神经退行性病变中野生型雄性C57BL / 6J小鼠的皮质和海马脑区。我们的研究结果表明，阿β（1-42）处理的小鼠具有增加的甲β具有增加沿寡聚体形成β分泌酶的表达。所述的增强的淀粉样途径β（1-42）处理的小鼠由于p53和3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）的表达增加而增强了脑胆固醇的积累。重要的是，我们通过在SH-SY5Y细胞中使用pifithrin- α（PFT）进一步证实了p53介导的HMGCR轴激活。此外，脑胆固醇水平升高也与OS升高有关。然而，QA给药于β（1-42）-injected小鼠显著改善的甲β通过上调的Nrf2 / HO-1途径阻止氧化应激负担，p53表达和胆固醇积累。此外，QA下调神经胶质增生，神经炎介质（对NF- κ B和IL-1 β），以及线粒体凋亡标记物（Bax，裂解的caspase-3和细胞色素c）的表达。QA治疗也逆转失调的突触标记（PSD-95和突触素）和改进在A空间学习和记忆的行为β -处理的小鼠脑。这些结果表明，一个β（1-42）可能是通过P53 / HMGCR轴的可能激活增加脑胆固醇水平引起认知功能的严重不利影响。然而，QA治疗降低胆固醇诱导的氧化应激，神经炎症，神经变性和，导致认知缺陷的后恢复β小鼠（1-42）脑室内注射。