ReferenceID 1516
Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid- β-Induced Mouse Model
Oxid Med Cell Longev
Alzheimer's disease (AD) is a progressive neurodegenerative disorder typified by several neuropathological features including amyloid-beta (Abeta) plaque and neurofibrillary tangles (NFTs). Cholesterol retention and oxid
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- Reference Id
- 1516
- Evidence Id
- 18106
- Core Evidence Id
- 18106
- Source Reference Id
- 3038
- Herb2 Reference Id
- HBREF003835
- Subject Paper Key
- HBIN020331_33274012
- Pubmed Id
- 33274012
- Doi
- 10.1155/2020/9523758
- Paper Title
- Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid- β-Induced Mouse Model
- Paper Abstract
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder typified by several neuropathological features including amyloid-beta (Abeta) plaque and neurofibrillary tangles (NFTs). Cholesterol retention and oxidative stress (OS) are the major contributors of elevated beta- and gamma-secretase activities, leading to excessive Abeta deposition, signifying the importance of altered cholesterol homeostasis and OS in the progression of Abeta-mediated neurodegeneration and cognitive deficit. However, the effect of Abeta 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 Abeta (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 Abeta (1-42)-treated mice have increased Abeta oligomer formation along with increased beta-secretase expression. The enhanced amyloidogenic pathway in Abeta (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-alpha (PFT) in SH-SY5Y cells. Furthermore, the augmented brain cholesterol levels were also associated with increased OS. However, the QA administration to Abeta (1-42)-injected mice significantly ameliorated the Abeta 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-kappaB and IL-1beta), 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 Abeta-treated mouse brains. These results suggest that Abeta (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 Abeta (1-42) i.c.v. injection in mice.
- Journal
- Oxid Med Cell Longev
- Publish Year
- 2020
- Experiment Subject
- mouse; sh-sy5y cells
- Experiment Type
- Animal Experiment
- Phenotype Related
- Neuroinflammation; Neurofibrillary Tangles; Neurodegeneration; Alzheimer's Disease; Cognitive Deficit; Neurodegenerative Disorder; Abeta-mediated Neurodegeneration
- Paper Title Cn
- Paper Title En
- Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid- β-Induced Mouse Model
- Bilingual Status
- semi_complete