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Involvement of Paired Immunoglobulin-like Receptor B in Diabetes-Associated Cognitive Dysfunction Through Modulation of Axon Outgrowth and Dendritic Remodeling

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Abstract

Type 2 diabetic patients have high risk of developing cognitive dysfunction, in which neural structural plasticity has played a pivotal role. Paired immunoglobulin-like receptor B (PirB), a receptor mainly expressed in neurons, acts as a critical inhibitor of neurite outgrowth and neural plasticity. However, the role of PirB in type 2 diabetes-associated cognitive dysfunction remains unknown. In this study, learning and memory impairment was observed in 24-week-old db/db mice by performing Morris water maze task, and the number of synapses along with the length of postsynaptic density by transmission electron microscopy were reduced in the hippocampus of db/db mice. Furthermore, PirB expression in the hippocampus of db/db mice was significantly upregulated using western blotting and immunofluorescence analysis. In cultured hippocampal neurons, high glucose treatment reduced the length of the longest neurite as well as axon initial segment (AIS), whereas silencing PirB expression rescued high glucose-induced neurite outgrowth inhibition, but not AIS. Additionally, cognitive deficits, dendrite morphology defects, and synapse-related proteins loss in db/db mice were alleviated when PirB knockdown was performed by adeno-associated virus injection. In conclusion, PirB is involved in diabetes-associated cognitive dysfunction through modulation of axon outgrowth and dendritic remodeling, providing a potential therapeutic target for diabetes-associated cognitive dysfunction.

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Availability of Data and Material

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability (Software Application or Custom Code)

GraphPad Prism Version 8.0; Image J Version 1.51 J.

Abbreviations

PirB:

Paired immunoglobulin-like receptor B

AD:

Alzheimer’s disease

LTP:

Long-term potentiation

LTD:

Long-term depression

MWM:

Morris water maze

AAV:

Adeno-associated virus

RIPA:

Radioimmunoprecipitation assay

SDS-PAGE:

SDS-polyacrylamide gel electrophoresis

PVDF:

Polyvinylidene fluoride

PSD:

Postsynaptic density

AIS:

Axon initial segment

PSD95:

Postsynaptic density protein 95

MAP2:

Microtubule-associated protein 2

βIII-tubulin:

Class III beta-tubulin

Syp:

Synaptophysin

α1-NaKA:

α1 Subunit of Na + /K + -ATPase

GAP43:

Growth-associated protein-43

RhoA:

Ras homolog gene family member A

POSH:

Plenty of SH3s

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Acknowledgements

The authors gratefully acknowledge Xiaoli Qu from the State Key Laboratory for Manufacturing Systems Engineering of Xi’an Jiaotong University for her help on image acquisition.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81774113, 81974540, 81901237), Beijing, China.

National Natural Science Foundation of China,81774113,Qiang Wang,81974540,Qiang Wang,81901237,Qian Zhai

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Authors and Affiliations

  1. Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China

    Kairui Pu, Meiyan Wu, Tao Jiang, Yuxin Zhang, Mao Ye, Jianyu Sun, Hongli Ma, Qian Zhai & Qiang Wang

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Contributions

Q.W., Q.Z., and K.R.P. conceptualized the study. K.R.P. and Q.Z. designed experiments and drafted the manuscript. K.R.P. performed experiments. M.Y.W., Y.X.Z., M.Y., and J.Y.S. assisted with experimental and execution. J.T. and H.L.M. were involved in data analysis. All authors read and approved the final manuscript.

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Correspondence to Qiang Wang.

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Efforts were made to minimize animal suffering and to reduce the number of animals used. All animal experiments were approved by the Institutional Animal Care and Use Committees of Xi’an Jiaotong University (Xi’an, China; 2019–060) in accordance with the National Institutes of Health guidelines.

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Q Z. and Q.W. contributed equally to this article.

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Pu, K., Wu, M., Jiang, T. et al. Involvement of Paired Immunoglobulin-like Receptor B in Diabetes-Associated Cognitive Dysfunction Through Modulation of Axon Outgrowth and Dendritic Remodeling. Mol Neurobiol 59, 2563–2579 (2022). https://doi.org/10.1007/s12035-021-02679-1

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