Dataset Information

Jujuboside A promotes A? clearance and ameliorates cognitive deficiency in Alzheimer's disease through activating Axl/HSP90/PPAR? pathway.

ABSTRACT: Rationale: It has been reported that peroxisome proliferator activated receptor ? (PPAR?) level decreases significantly in the brains of Alzheimer's disease (AD) patients and mice models, while the mechanism is unclear. This study aims to unravel the mechanism that amyloid ? (A?) decreases PPAR? and attempted to discover lead compound that preserves PPAR?. Methods: In APP/PS1 transgenic mice and A? treated microglia, the interaction between HSP90 and PPAR? were analyzed by western blot. Using a PPRE (PPAR? responsive element) containing reporter cell line, compounds that activate PPAR? activity were identified. After genetic ablation or pharmacological inhibition of potential target pathways, the target of jujuboside A (JuA) was discovered through Axl/HSP90?. After oral administration or intrathecal injection, the anti-AD activity of JuA was evaluated by Morris water maze (MWM) test and object recognition test. Soluble A?42 levels and plaque numbers after JuA treatment were detected by thioflavin S staining, and the activation of microglia was assayed by immunofluorescence staining against Iba-1. Results: We found that A? stress decreased heat shock protein 90 ? (HSP90?), subsequently reduced the abundance of PPAR?, and down-regulated A? clearance-related genes in BV2 cells and primary microglia. We identified that JuA stimulated the expression of HSP90?, strengthened the interaction between HSP90? and PPAR?, preserved PPAR? levels, and thus effectively promoted the clearance of A?42. We demonstrated that JuA increased HSP90? expression through Axl/ERK pathway. JuA significantly ameliorated cognitive deficiency in APP/PS1 transgenic mice, meanwhile, JuA significantly reduced the soluble A?42 levels and plaque numbers in the brain. Notably, the therapeutic effects of JuA were dampened by R428, an Axl inhibitor. Conclusions: This study suggests that the up-regulation of HSP90? by JuA through Axl is a potential therapeutic strategy to facilitate A?42 clearance and ameliorate cognitive deficiency in AD.

SUBMITTER: Zhang M

PROVIDER: S-EPMC6096387 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Jujuboside A promotes Aβ clearance and ameliorates cognitive deficiency in Alzheimer's disease through activating Axl/HSP90/PPARγ pathway.

Zhang Mu M Qian Cheng C Zheng Zu-Guo ZG Qian Fei F Wang Yanyan Y Thu Pyone Myat PM Zhang Xin X Zhou Yaping Y Tu Lifan L Liu Qingling Q Li Hui-Jun HJ Yang Hua H Li Ping P Xu Xiaojun X

Theranostics 20180730 15

<b>Rationale:</b> It has been reported that peroxisome proliferator activated receptor γ (PPARγ) level decreases significantly in the brains of Alzheimer's disease (AD) patients and mice models, while the mechanism is unclear. This study aims to unravel the mechanism that amyloid β (Aβ) decreases PPARγ and attempted to discover lead compound that preserves PPARγ. <b>Methods:</b> In APP/PS1 transgenic mice and Aβ treated microglia, the interaction between HSP90 and PPARγ were analyzed by western ...[more]

PMID: 30128052

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Project description:Jujuboside B has been reported to have protective effect on many cardiovascular diseases. However, the effects of Jujuboside B on vascular tension and endothelial function are unknown. The present study investigated the effects of Jujuboside B on reducing vascular tension, protecting endothelial function and the potential mechanisms. The tension of isolated rat thoracic aorta ring was measured by Wire myograph system. The concentration of nitric oxide (NO) and the activity of endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells (HAECs) were determined by Griess reagent method and enzyme-linked immune sorbent assay. The protein levels of eNOS and p-eNOS at Serine-1177 were determined by western blot analysis. Intracellular Ca2+ concentration in HAECs was measured by laser confocal imaging microscopy. Results showed that Jujuboside B reduced the tension of rat thoracic aorta rings with intact endothelium in a dose-dependent manner. L-NAME, KN93, EGTA, SKF96365, iberiotoxin and glibenclamide significantly attenuated Jujuboside B-induced vasodilation in endothelium-intact tissues. In contrast, indometacin and 4-DAMP had no such effects. Jujuboside B also promoted NO generation and increased eNOS activity, which were attenuated by L-NAME, EGTA and SKF96365. Moreover, Jujuboside B increased intracellular Ca2+ concentration dose-dependently, which was inhibited by EGTA and SKF96365. Besides, Jujuboside B induced a rapid Ca2+ influx instantaneously after depleting intracellular Ca2+ store, which was significantly inhibited by SKF96365. In conclusion, this study preliminarily confirmed that Jujuboside B reduced vascular tension endothelium-dependently. The underlying mechanisms involved that Jujuboside B increased extracellular Ca2+ influx through endothelial transient receptor potential cation (TRPC) channels, phosphorylated eNOS and promoted NO generation in vascular endothelial cells. In addition, Jujuboside B-induced vasodilation involved endothelium-dependent hyperpolarizaiton through endothelial potassium channels. Jujuboside B is a natural compound with new pharmacological effects on improving endothelial dysfunction and treating vascular diseases.

Dataset Information

Jujuboside A promotes A? clearance and ameliorates cognitive deficiency in Alzheimer's disease through activating Axl/HSP90/PPAR? pathway.

Publications

Jujuboside A promotes Aβ clearance and ameliorates cognitive deficiency in Alzheimer's disease through activating Axl/HSP90/PPARγ pathway.

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