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Effects of Porphyromonas gingivalis and Its Underlying Mechanisms on Alzheimer-Like Tau Hyperphosphorylation in Sprague-Dawley Rats

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Abstract

Hyperphosphorylated tau is the main component of neurofibrillary tangles and involved in the pathogenesis of Alzheimer’s disease (AD). Increasing evidences suggest close associations between Porphyromonas gingivalis (P. gingivalis) and AD, but the relationship between P. gingivalis and tau hyperphosphorylation is still unclear. In this study, we investigated whether peripheral infection with P. gingivalis caused tau hyperphosphorylation by using wild Sprague-Dawley (SD) rats and HT-22 cells. The rats were injected with P. gingivalis suspension or phosphate-buffered saline 3 times per week. After 4 weeks or 12 weeks, the rats were sacrificed for analyzing systemic inflammation, neuroinflammation, and tau hyperphosphorylation. The results showed that the severity of phosphorylated tau at the AD-related sites Thr181 and Thr231 and the number of activated astrocytes were notably greater in the hippocampus of rats with P. gingivalis injection. And the levels of the inflammatory cytokines interleukin (IL)-1β and IL-6 and tumor necrosis factor-α in serum and hippocampus were also increased in the rats with P. gingivalis injection. In addition, the activity of protein phosphatase 2A (PP2A) was significantly inhibited in the hippocampus of rats with P. gingivalis injection. In vitro, IL-1β induced tau hyperphosphorylation by inhibiting the activity of PP2A in HT-22 cells and application of the PP2A promoter efficiently attenuated IL-1β-induced tau hyperphosphorylation in HT-22 cells. These results indicated that P. gingivalis could induce tau hyperphosphorylation via, in part, attenuating the activity of PP2A through triggering systemic inflammation and neuroinflammation in wild-type SD rats.

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Data Availability

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

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Acknowledgments

We thank MD Fu-Lei Zeng and PhD Sha-Sha Yuan for their help with the experiments and State Key Laboratory of Oral Diseases for P. gingivalis strain.

Funding

This work was supported by a research grant from Sichuan Province Science and technology key research and development program, Chengdu, China (grant no. 2018SZ0163), and Geriatric Health Care and Medical Research Center, Sichuan University, Chengdu, Sichuan Province, China.

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Author notes

  1. Zhiqun Tang and Dan Liang contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Section 3, South Renmin Road, Chengdu, 610041, Sichuan, People’s Republic of China

    Zhiqun Tang, Miaoying Cheng, Xinyi Su, Runhe Liu, Yiding Zhang & Hongkun Wu

  2. Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China

    Dan Liang

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  1. Zhiqun Tang
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Contributions

All authors contributed to the study conception and design. Hongkun Wu was responsible for conceiving, designing, and supervising the present study, and revising the manuscript. Material preparation, data collection, and analysis were performed by Zhiqun Tang, Dan Liang, Miaoying Cheng, Xinyi Su, Runhe Liu, and Yiding Zhang. The first draft of the manuscript was written by Zhiqun Tang and Dan Liang; all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hongkun Wu.

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All animal experiments were conducted at State Key Laboratory of Oral Diseases and were licensed by Research Ethics Committee of West China Hospital of Stomatology (No. WCHSIRB-D-2017-001).

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Tang, Z., Liang, D., Cheng, M. et al. Effects of Porphyromonas gingivalis and Its Underlying Mechanisms on Alzheimer-Like Tau Hyperphosphorylation in Sprague-Dawley Rats. J Mol Neurosci 71, 89–100 (2021). https://doi.org/10.1007/s12031-020-01629-1

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