Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid-β-Induced Mouse Model
Joint Authors
Hahm, Jong Ryeal
Saeed, Kamran
Shah, Shahid Ali
Ullah, Rahat
Alam, Sayed Ibrar
Park, Jun Sung
Saleem, Samreen
Jo, Myeung Hoon
Kim, Min Woo
Kim, Myeong Ok
Source
Oxidative Medicine and Cellular Longevity
Issue
Vol. 2020, Issue 2020 (31 Dec. 2020), pp.1-20, 20 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2020-11-21
Country of Publication
Egypt
No. of Pages
20
Main Subjects
Abstract EN
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.
American Psychological Association (APA)
Saeed, Kamran& Shah, Shahid Ali& Ullah, Rahat& Alam, Sayed Ibrar& Park, Jun Sung& Saleem, Samreen…[et al.]. 2020. Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid-β-Induced Mouse Model. Oxidative Medicine and Cellular Longevity،Vol. 2020, no. 2020, pp.1-20.
https://search.emarefa.net/detail/BIM-1206071
Modern Language Association (MLA)
Saeed, Kamran…[et al.]. Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid-β-Induced Mouse Model. Oxidative Medicine and Cellular Longevity No. 2020 (2020), pp.1-20.
https://search.emarefa.net/detail/BIM-1206071
American Medical Association (AMA)
Saeed, Kamran& Shah, Shahid Ali& Ullah, Rahat& Alam, Sayed Ibrar& Park, Jun Sung& Saleem, Samreen…[et al.]. Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid-β-Induced Mouse Model. Oxidative Medicine and Cellular Longevity. 2020. Vol. 2020, no. 2020, pp.1-20.
https://search.emarefa.net/detail/BIM-1206071
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1206071