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Xanthoceraside modulates NR2B-containing NMDA receptors at synapses and rescues learning-memory deficits in APP/PS1 transgenic mice

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Abstract

Rationale

Alzheimer’s disease (AD) is characterized by memory loss and synaptic damage. Previous studies suggested that xanthoceraside decreases glutamate-induced PC12 cell death, ameliorates memory deficits, and increases the number of dendritic spines in AD mice. These results indicated that xanthoceraside might have activities that protect synaptic plasticity. Herein, we detected the effect of xanthoceraside on synaptic function.

Materials and methods

Three-month-old APP/PS1 transgenic mice were orally treated with xanthoceraside (0.02, 0.08, or 0.32 mg/kg) once daily for 4 months and then behavioral tests were performed. LTP and Fluo-4/AM were carried out in vivo and in vitro, respectively. CaMKII-GluR1 and NR2B-associated proteins on synapses were measured.

Results

Xanthoceraside administration alleviated learning-memory deficits and increased the LTP in APP/PS1 transgenic mice. Meanwhile, xanthoceraside increased the expression of pT286-CaMKII in synaptic and extrasynaptic pools and CaMKII, pS831-GluR1, and GluR1 in synaptic pools. In addition, xanthoceraside increased the total pY1472-NR2B and NR2B expression and increased the levels of pY1472-NR2B in synaptic and extrasynaptic pools and NR2B in synaptic pools. However, NR2B was decreased in extrasynaptic pools, which might be associated with decreased expression of STEP61 and pY531-Fyn. In vitro studies showed that xanthoceraside inhibited intracellular calcium overload and increased the number of and extended the length of dendrites in primary hippocampal neurons compared with the Aβ25–35 group.

Conclusions

The mechanism of xanthoceraside on ameliorating learning-memory deficits might be related to decrease intracellular calcium overload, increase CaMKII-GluR1 proteins, and up-regulate trafficking of pY1472-NR2B at synapse, thereby improving LTP in APP/PS1 transgenic mice.

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Acknowledgements

This study was supported by the Research Fund for National Natural Science Foundation of China (No. 81373992) and the Joint Founds of NSFC-Liaoning (U1508220).

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Authors and Affiliations

  1. Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People’s Republic of China

    Lin Zhu, Lei Yang, Xuemei Zhao, Danyang Liu, Xiaoli Guo, Peng Liu, Tianyan Chi, Xuefei Ji & Libo Zou

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  1. Lin Zhu
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  2. Lei Yang
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  3. Xuemei Zhao
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  4. Danyang Liu
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  5. Xiaoli Guo
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  6. Peng Liu
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  7. Tianyan Chi
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  8. Xuefei Ji
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  9. Libo Zou
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Contributions

L. Zhu conceived the experiments, contributed to research data, and drafted the manuscript; X. Ji, T. Chi, and P. Liu revised the manuscript. X. Zhao, L. Yang, and D. Liu contributed to technical assistance. X. Guo contributed to raise animals. L. Zou revised the manuscript and supervised the analysis.

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Correspondence to Libo Zou.

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Zhu, L., Yang, L., Zhao, X. et al. Xanthoceraside modulates NR2B-containing NMDA receptors at synapses and rescues learning-memory deficits in APP/PS1 transgenic mice. Psychopharmacology 235, 337–349 (2018). https://doi.org/10.1007/s00213-017-4775-6

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