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Activation of the Hippocampal LXRβ Improves Sleep-Deprived Cognitive Impairment by Inhibiting Neuroinflammation

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Abstract

Sleep deprivation (SD) leads to cognitive impairment due to neuroinflammation associated with impaired hippocampal neuronal plasticity and memory processes. Liver X receptors (LXRs), including LXRα and LXRβ isoforms, are crucial for synaptic plasticity and neuroinflammation. However, the potential roles of LXRs in the pathogenesis of cognitive impairment induced by SD remain unclear. We revealed that SD resulted in LXRβ reduction in the hippocampus, which was associated with upregulated expression of high mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4)/NF-κB p65, and knockdown of hippocampal LXRβ by shRNA (shLXRβ) led to cognitive impairment. GW3965, a dual agonist for both LXRα and LXRβ, ameliorated SD-induced cognitive impairment by inhibiting microglia activation, suppressing HMGB1/TLR4/NF-κB p65 pathway, and ultimately affecting the hippocampal expression of inflammatory cytokines in SD mice. LXRβ knockdown by shLXRβ abrogated the GW3965-mediated inhibition of the HMGB1/TLR4/NF-κB p65 pathway, therefore, abolishing the cognitive improvement. Moreover, inhibition of HMGB1 by glycyrrhizin (GLY) synergistic promoted GW3965-mediated anti-inflammation in activated microglia after lipopolysaccharide (LPS)/ATP stimulation and facilitated the cognitive improvement after GW administration by activating LXRβ. All the data suggested that GW3965 ameliorated impaired cognition in SD mice by suppressing the HMGB1/TLR4/NF-κB p65 pathway followed LXRβ activation. This study correlates a deficit of LXRβ in cognitive dysfunction in SD associated with HMGB1 inflammatory pathway in hippocampus, and LXRs may serve as a potential therapeutic target for cognitive impairment with anti-inflammation.

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Acknowledgements

The authors thank Wen-Ju Wang for his great help in analyzing the data.

Availability of Data and Materials

Datasets from this study are available from the corresponding author on reasonable request.

Funding

This study was funded by the National Natural Science Foundation of China (no. 82071515), Key International Cooperation Projects of Shaanxi Province (no. 2020KWZ-021), Military Medicine Promotion Projects (no. 2018jsts09) for Professor Wu, and Research Foundation from Social Development Science and Technology Project of Shaanxi Province for Mr. Wang (no. 2020JQ-464).

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Author notes

  1. Chen Qiu and Min Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China, 710032

    Chen Qiu, Min Wang, Wen Yu, Zheng Rong, He-Sheng Zheng, Ting Sun, Shui-Bing Liu, Ming-Gao Zhao & Yu-Mei Wu

  2. Department of Acupuncture-moxibustion-massage, Shaanxi University of Chinese Medicine, Xi’an, Shaanxi Province, People’s Republic of China, 712000

    Zheng Rong & He-Sheng Zheng

  3. Department of Pharmacy, Precision Pharmacy & Drug Development Center, The Second Affiliated Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China, 710038

    Ming-Gao Zhao

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  1. Chen Qiu
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Contributions

Chen Qiu and Min Wang wrote the manuscript. Wen Yu and Zheng Rong developed the model and performed part of the behavior tests. He-Sheng Zheng and Ting Sun participated in the western blot and ELISA analyses. Min Wang was responsible for immunohistochemical experiments. Chen Qiu was responsible for cell culture, stereotaxic surgery, and microinjections. Shui-Bing Liu and Ming-Gao Zhao analyzed the data. Chen Qiu and Yu-Mei Wu designed and supervised whole experiments. All authors approved the final manuscript.

Corresponding author

Correspondence to Yu-Mei Wu.

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Ethics Approval

All experimental procedures were approved by the Ethics Committee of Fourth Military Medical University (approval reference number no. KY20193145) in full accordance with the ethical guidelines of the National Institutes of Health for the care and use of laboratory animals.

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Supplementary Information

Figure S1

SD decreased the expression of LXRβ and increased the expression of microglia in hippocampus. The expression of LXRβ and Iba-1were measured by immunostaining. LXRβ was labeled in red, Iba-1 was labeled in green and the nucleus was labeled in blue. The expression of LXRβ in hippocampus was decreased upon SD while the expression of Iba-1was increased. (PNG 2610 kb)

High Resulotion (TIF 3482 kb)

Figure S2

LXRβ was present in microglia. Representative images of LXRβ in microglia in mice hippocampus from SD. LXRβ was labeled in red, Iba-1 was labeled in green, and the nucleus was labeled in blue. (PNG 657 kb)

High Resulotion (TIF 960 kb)

Figure S3

GW3965 dose-dependently reduced LPS/ATP-induced microglia activation. (a) Representative results of western blot analysis for Iba-1 and CD68 (a marker of activated microglia), GW dose-dependently reduced the expression of (b) Iba-1 and (c) CD68 induced by LPS/ATP. n = 6 in each group, ***p < 0.001, compared with the Ctrl group; ###p < 0.001, compared with the LPS/ATP group. (PNG 152 kb)

High Resulotion (TIF 341 kb)

Figure S4

GW3965 suppressed the increased levels of HMGB1, TNF-α and IL-1β in supernatants by activating LXRβ. The expression of (a) HMGB1, (b) TNF-α and (c) IL-1β in supernatants from each group was evaluated by ELISA assay. n = 6 in each group, ***p < 0.001, compared with the shNC group; ###p < 0.001, compared with the shNC + LPS/ATP group; $$$p < 0.001, compared with the shNC + LPS/ATP + GW group. (PNG 87 kb)

High Resulotion (TIF 263 kb)

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Qiu, C., Wang, M., Yu, W. et al. Activation of the Hippocampal LXRβ Improves Sleep-Deprived Cognitive Impairment by Inhibiting Neuroinflammation. Mol Neurobiol 58, 5272–5288 (2021). https://doi.org/10.1007/s12035-021-02446-2

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