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Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid-?-Induced Mouse Model.

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder typified by several neuropathological features including amyloid-beta (A?) plaque and neurofibrillary tangles (NFTs). Cholesterol retention and oxidative stress (OS) are the major contributors of elevated ?- and ?-secretase activities, leading to excessive A? deposition, signifying the importance of altered cholesterol homeostasis and OS in the progression of A?-mediated neurodegeneration and cognitive deficit. However, the effect of A? 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 A? (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 A? (1-42)-treated mice have increased A? oligomer formation along with increased ?-secretase expression. The enhanced amyloidogenic pathway in A? (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-? (PFT) in SH-SY5Y cells. Furthermore, the augmented brain cholesterol levels were also associated with increased OS. However, the QA administration to A? (1-42)-injected mice significantly ameliorated the A? 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-?B and IL-1?), 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 A?-treated mouse brains. These results suggest that A? (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 A? (1-42) i.c.v. injection in mice.

SUBMITTER: Saeed K

PROVIDER: S-EPMC7700034 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid-β-Induced Mouse Model.

Saeed Kamran K Shah Shahid Ali SA Ullah Rahat R Alam Sayed Ibrar SI Park Jun Sung JS Saleem Samreen S Jo Myeung Hoon MH Kim Min Woo MW Hahm Jong Ryeal JR Kim Myeong Ok MO

Oxidative medicine and cellular longevity 20201120

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 ...[more]

PMID: 33274012

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Project description:Familial early-onset forms of Alzheimer's disease (AD) are linked to overproduction of amyloid beta (Aβ) peptides, while decreased clearance of Aβ is the driving force leading to its toxic accumulation in late-onset (sporadic) AD. Oxidative modifications and defective function have been reported in Aβ-degrading proteases such as neprilysin (NEP) and insulin-degrading enzyme (IDE). However, the exact mechanisms that regulate the proteolytic clearance of Aβ and its deficits are largely unknown. We have previously showed that cellular cholesterol loading, by depleting the mitochondrial GSH (mGSH) content, stimulates Αβ-induced mitochondrial oxidative stress and promotes AD-like pathology in APP-PSEN1-SREBF2 mice. Here, using the same AD mouse model we examined whether cholesterol-enhanced mitochondrial oxidative stress affects NEP and IDE function. We found that brain extracts from APP-PSEN1-SREBF2 mice displayed increased presence of oxidatively modified forms of NEP and IDE, associated with impaired enzymatic activities. Both alterations were substantially recovered after an in vivo treatment with the cholesterol-lowering agent 2-hydroxypropyl-β-cyclodextrin. The recovery of the proteolytic activity after treatment was accompanied with a significant reduction of Aβ levels. Supporting these results, cholesterol-enriched SH-SY5Y cells were more sensitive to Aβ-induced impairment of IDE and NEP function in vitro. The rise of cellular cholesterol also stimulated the extracellular release of IDE by an unconventional autophagy-coordinated mechanism. Recovery of depleted pool of mGSH in these cells not only prevented the detrimental effect of Aβ on intracellular AβDPs activities but also had an impact on extracellular IDE levels and function, stimulating the extracellular Aβ degrading activity. Therefore, changes in brain cholesterol levels by modifying the mGSH content would play a key role in IDE and NEP-mediated proteolytic elimination of Aβ peptides and AD progression.

Project description:Age-related decline in mitochondrial function and oxidative stress plays a critical role in neurodegeneration. Lactate dehydrogenase-B (LDHB) is a glycolytic enzyme that catalyzes the conversion of lactate, an important brain energy substrate, into pyruvate. It has been reported that the LDHB pattern changes in the brain during ageing. Yet very little is known about the effect of LDHB deficiency on brain pathology. Here, we have used Ldhb knockout (Ldhb-/-) mice to test the hypothesis that LDHB deficiency plays an important role in oxidative stress-mediated neuroinflammation and neurodegeneration. LDHB knockout (Ldhb-/-) mice were generated by the ablation of the Ldhb gene using the Cre/loxP-recombination system in the C57BL/6 genetic background. The Ldhb-/- mice were treated with either osmotin (15 μg/g of the body; intraperitoneally) or vehicle twice a week for 5-weeks. After behavior assessments, the mice were sacrificed, and the cortical and hippocampal brain regions were analyzed through biochemical and morphological analysis. Ldhb-/- mice displayed enhanced reactive oxygen species (ROS) and lipid peroxidation (LPO) production, and they revealed depleted stores of cellular ATP, GSH:GSSG enzyme ratio, and downregulated expression of Nrf2 and HO-1 proteins, when compared to WT littermates. Importantly, the Ldhb-/- mice showed upregulated expression of apoptosis mediators (Bax, Cytochrome C, and caspase-3), and revealed impaired p-AMPK/SIRT1/PGC-1alpha signaling. Moreover, LDHB deficiency-induced gliosis increased the production of inflammatory mediators (TNF-α, Nf-ĸB, and NOS2), and revealed cognitive deficits. Treatment with osmotin, an adipoR1 natural agonist, significantly increased cellular ATP production by increasing mitochondrial function and attenuated oxidative stress, neuroinflammation, and neuronal apoptosis, probably, by upregulating p-AMPK/SIRT1/PGC-1alpha signaling in Ldhb-/- mice. In brief, LDHB deficiency may lead to brain oxidative stress-mediated progression of neurodegeneration via regulating p-AMPK/SIRT1/PGC-1alpha signaling, while osmotin could improve mitochondrial functions, abrogate oxidative stress and alleviate neuroinflammation and neurodegeneration in adult Ldhb-/- mice.

Dataset Information

Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid-?-Induced Mouse Model.

Publications

Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid-<i>β</i>-Induced Mouse Model.

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