Magnolol alleviates Alzheimer's disease-like pathology in transgenic C. elegans by promoting microglia phagocytosis and the degradation of beta-amyloid through activation of PPAR-γ

Xie, Zhishen; Zhao, Jianping; Wang, Hui; Jiang, Yali; Yang, Qiaoling; Fu, Yu; Zeng, Hu; Hölscher, Christian; Xu, Jiangyan; Zhang, Zhenqiang

doi:10.1016/j.biopha.2020.109886

Cited by 58 publications

(41 citation statements)

References 51 publications

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“…LPL is a downstream target gene of lipid-activated transcription factor PPARγ, which has been reported to be implicated in the progression of AD (Medrano-Jiménez et al, 2019;Chamberlain et al, 2020;Kotha et al, 2020;Xie et al, 2020). This study demonstrated that the expression of PPARγ was decreased in SHSY5Y cells exposed to 2 µM Aβ, and increased in cells with 10 µM Aβ exposure.…”

Section: Discussionmentioning

confidence: 53%

Exploration of the Molecular Mechanism for Lipoprotein Lipase Expression Variations in SH-SY5Y Cells Exposed to Different Doses of Amyloid-Beta Protein

Zhang

Liu

Wang

et al. 2020

Front. Aging Neurosci.

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Progressive accumulation of amyloid-β (Aβ) plaques in the brain is a characteristic pathological change in Alzheimer's disease (AD). We previously found the expression of lipoprotein lipase (LPL) was increased in SH-SY5Y cells exposed to low-dose Aβ and decreased in cells with high-dose Aβ exposure, but the molecular mechanism is still unclear. Based on previous studies, the opposite regulation of histone deacetylase2 (HDAC2) and HDAC3 on LPL expression probably explain the above molecular mechanism, in which microRNA-29a and peroxisome proliferator-activated receptor γ (PPARγ) may be involved. This study further revealed the mechanism of HDAC2 and HDAC3 on conversely regulating LPL expression. The results showed that HDAC2 down-regulated microRNA-29a by decreasing histone acetylation (Ace-H3K9) level in its promoter region, subsequently increasing LPL expression directly or through PPARγ/LPL pathway; HDAC3 decreased LPL expression through inhibiting Ace-H3K9 levels in LPL and PPARγ promoter regions and up-regulating microRNA-29a. This study also found that with increasing concentrations of Aβ in cells, HDAC2 and HDAC3 expression were gradually increased, and Ace-H3K9 levels in LPL and PPARγ promoter region regulated by HDAC3 were decreased correspondingly, while Ace-H3K9 levels in microRNA-29a promoter region modulated by HDAC2 were not decreased gradually but presented a U-shaped trend. These may lead to the results that a U-shaped alteration in microRNA-29a expression, subsequently leading to an inverse U-shaped alteration in PPARγ or LPL expression. In conclusion, HDAC2 and HDAC3 at least partly mediate LPL expression variations in different concentrations of Aβ exposed SH-SY5Y cells, in which microRNA-29a and PPARγ are involved, and the histone acetylation level in microRNA-29a promoter region plays a key role.

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Section: Discussionmentioning

confidence: 53%

Exploration of the Molecular Mechanism for Lipoprotein Lipase Expression Variations in SH-SY5Y Cells Exposed to Different Doses of Amyloid-Beta Protein

Zhang

Liu

Wang

et al. 2020

Front. Aging Neurosci.

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“…PPAR-γ activation led to the inhibition of the DNA-binding activity of NF-κB hence attenuated inflammation response. A concentration of 2.5 µM of magnolol significantly inhibited the transcriptional activity of NF-κB in the HEK293 T cells, a cell line derived from the human embryonic kidney that were transfected with NF-κB reporter plasmids [ 238 ]. The relative luciferase activity of NF-κB in magnolol treated cells (3.5-fold) was significantly lower compared to control (5.5-fold).…”

Section: Oxidative Stress and Intracellular Signaling Pathwaymentioning

confidence: 99%

“…In addition, magnolol markedly reduced the mRNA expressions of the downstream targeted genes by NF-κB such as iNOS (0.75), TNF-α (0.75), and IL-1β (0.55) in BV2 cells that were pre-treated with oligomeric Aβ42 ( p < 0.05). The anti-inflammatory effects of magnolol in this study were reversed with the addition of GW9662, a potent antagonist of PPAR-γ [ 238 ].…”

Section: Oxidative Stress and Intracellular Signaling Pathwaymentioning

confidence: 99%

A Mechanistic Evaluation of Antioxidant Nutraceuticals on Their Potential against Age-Associated Neurodegenerative Diseases

et al. 2020

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Nutraceuticals have been extensively studied worldwide due to its neuroprotective effects in in vivo and in vitro studies, attributed by the antioxidative properties. Alzheimer (AD) and Parkinson disease (PD) are the two main neurodegenerative disorders that are discussed in this review. Both AD and PD share the similar involvement of oxidative stress in their pathophysiology. Nutraceuticals exert their antioxidative effects via direct scavenging of free radicals, prevent damage to biomolecules, indirectly stimulate the endogenous antioxidative enzymes and gene expressions, inhibit activation of pro-oxidant enzymes, and chelate metals. In addition, nutraceuticals can act as modulators of pro-survival, pro-apoptotic, and inflammatory signaling pathways. They have been shown to be effective particularly in preclinical stages, due to their multiple mechanisms of action in attenuating oxidative stress underlying AD and PD. Natural antioxidants from food sources and natural products such as resveratrol, curcumin, green tea polyphenols, and vitamin E are promising therapeutic agents in oxidative stress-mediated neurodegenerative disease as they have fewer adverse effects, more tolerable, cheaper, and sustainable for long term consumption.

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“…MN has been shown to exert various pharmacological activities such as antiinflammation [14], antioxidation [15], and neuroprotection [16,17]. MN has recently been reported to possess anti-AD effects in experimental models of AD [18][19][20]. MN significantly alleviates the Aβ-induced neurotoxicity via suppressing the intracellular calcium elevation, the reactive oxygen species production, the caspase-3 activity, and inflammation, as well as promoting the phagocytosis and degradation of Aβ [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

“…MN has recently been reported to possess anti-AD effects in experimental models of AD [ 18 – 20 ]. MN significantly alleviates the A β -induced neurotoxicity via suppressing the intracellular calcium elevation, the reactive oxygen species production, the caspase-3 activity, and inflammation, as well as promoting the phagocytosis and degradation of A β [ 18 – 20 ]. In addition, MN has been shown to prevent the cognitive deficits induced by scopolamine in mice via inhibition of the acetylcholinesterase activity and oxidative stress [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Magnolol Ameliorates Behavioral Impairments and Neuropathology in a Transgenic Mouse Model of Alzheimer’s Disease

Xian

Liu

et al. 2020

Oxidative Medicine and Cellular Longevity

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Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by progressive memory loss. Magnolol (MN), the main active ingredient of Magnolia officinalis, possesses anti-AD effects in several experimental models of AD. In this study, we aimed to explore whether MN could ameliorate the cognitive deficits in TgCRND8 transgenic mice and to elucidate its molecular mechanisms. Male TgCRND8 mice were orally administered with MN (20 and 40 mg/kg) daily for 4 consecutive months, followed by assessing the spatial learning and memory functions using the open-field, radial arm maze, and novel object recognition tests. The results demonstrated that MN (20 and 40 mg/kg) could markedly ameliorate the cognitive deficits in TgCRND8 mice. In addition, MN significantly increased the expression of postsynaptic density protein 93 (PSD93), PSD-95, synapsin-1, synaptotagmin-1, synaptophysin (SYN), and interleukin-10 (IL-10), while markedly reduced the protein levels of tumor necrosis factor alpha (TNF-α), IL-6, IL-1β, Aβ40, and Aβ42, and modulated the amyloid precursor protein (APP) processing and phosphorylation. Immunofluorescence showed that MN significantly suppressed the activation of microglia (Iba-1) and astrocytes (GFAP) in the hippocampus and cerebral cortex of TgCRND8 mice. Mechanistic studies revealed that MN could significantly increase the ratios of p-GSK-3β (Ser9)/GSK-3β, p-Akt (Ser473)/Akt, and p-NF-κB p65/NF-κB p65. These findings indicate that MN exerted cognitive deficits improving effects via suppressing neuroinflammation, amyloid pathology, and synaptic dysfunction through regulating the PI3K/Akt/GSK-3β and NF-κB pathways, suggesting that MN is a promising naturally occurring polyphenol worthy of further developing into a therapeutic agent for AD treatment.

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Magnolol alleviates Alzheimer's disease-like pathology in transgenic C. elegans by promoting microglia phagocytosis and the degradation of beta-amyloid through activation of PPAR-γ

Cited by 58 publications

References 51 publications

Exploration of the Molecular Mechanism for Lipoprotein Lipase Expression Variations in SH-SY5Y Cells Exposed to Different Doses of Amyloid-Beta Protein

Exploration of the Molecular Mechanism for Lipoprotein Lipase Expression Variations in SH-SY5Y Cells Exposed to Different Doses of Amyloid-Beta Protein

A Mechanistic Evaluation of Antioxidant Nutraceuticals on Their Potential against Age-Associated Neurodegenerative Diseases

Magnolol Ameliorates Behavioral Impairments and Neuropathology in a Transgenic Mouse Model of Alzheimer’s Disease

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