Skip to main content

Advertisement

SpringerLink
Log in

Up-Regulation of Trem2 Inhibits Hippocampal Neuronal Apoptosis and Alleviates Oxidative Stress in Epilepsy via the PI3K/Akt Pathway in Mice

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Epilepsy is a chronic and severe neurological disorder that has negative effects on the autonomous activities of patients. Functionally, Trem2 (triggering receptor expressed on myeloid cells-2) is an immunoglobulin receptor that affects neurological and psychiatric genetic diseases. Based on this rationale, we aimed to assess the potential role of Trem2 integration with the PI3K/Akt pathway in epilepsy. We used microarray-based gene expression profiling to identify epilepsy-related differentially-expressed genes. In a mouse hippocampal neuron model of epilepsy, neurons were treated with low-Mg2+ extracellular fluid, and the protein and mRNA expression of Trem2 were determined. Using a gain-of-function approach with Trem2, neuronal apoptosis and its related factors were assessed by flow cytometry, RT-qPCR, and Western blot analysis. In a pilocarpine-induced epileptic mouse model, the malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) content and superoxide dismutase (SOD) and glutathione-peroxidase (GSH-Px) activity in the hippocampus were determined, and the protein expression of Trem2 was measured. In addition, the regulatory effect of Trem2 on the PI3K/Akt pathway was analyzed by inhibiting this pathway in both the cell and mouse models of epilepsy. Trem2 was found to occupy a core position and was correlated with epilepsy. Trem2 was decreased in the hippocampus of epileptic mice and epileptic hippocampal neurons. Of crucial importance, overexpression of Trem2 activated the PI3K/Akt pathway to inhibit neuronal apoptosis. Moreover, activation of the PI3K/Akt pathway through over-expression of Trem2 alleviated oxidative stress, as shown by the increased expression of SOD and GSH-Px and the decreased expression of MDA and 8-OHdG. The current study defines the potential role of Trem2 in inhibiting the development of epilepsy, indicating that Trem2 up-regulation alleviates hippocampal neuronal injury and oxidative stress, and inhibits neuronal apoptosis in epilepsy by activating the PI3K/Akt pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014, 55: 475–482.

    Article  PubMed  Google Scholar 

  2. Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA. Glia and epilepsy: excitability and inflammation. Trends Neurosci 2013, 36: 174–184.

    Article  CAS  PubMed  Google Scholar 

  3. Moshe SL, Perucca E, Ryvlin P, Tomson T. Epilepsy: new advances. Lancet 2015, 385: 884–898.

    Article  PubMed  Google Scholar 

  4. Newton CR, Garcia HH. Epilepsy in poor regions of the world. Lancet 2012, 380: 1193–1201.

    Article  PubMed  Google Scholar 

  5. Jacobs J, Staba R, Asano E, Otsubo H, Wu JY, Zijlmans M, et al. High-frequency oscillations (HFOs) in clinical epilepsy. Prog Neurobiol 2012, 98: 302–315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wykes RC, Heeroma JH, Mantoan L, Zheng K, MacDonald DC, Deisseroth K, et al. Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy. Sci Transl Med 2012, 4: 161ra152.

  7. Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, et al. Coding variants in TREM2 increase risk for Alzheimer’s disease. Hum Mol Genet 2014, 23: 5838–5846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Benitez BA, Cooper B, Pastor P, Jin SC, Lorenzo E, Cervantes S, et al. TREM2 is associated with the risk of Alzheimer’s disease in Spanish population. Neurobiol Aging 2013, 34: 1711 e1715–1717.

    Google Scholar 

  9. Fu Y, Zhu H, Wu W, Xu J, Chen T, Xu B, et al. Clinical significance of lymphoid enhancer-binding factor 1 expression in acute myeloid leukemia. Leuk Lymphoma 2014, 55: 371–377.

    Article  CAS  PubMed  Google Scholar 

  10. Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 2005, 201: 647–657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kawabori M, Kacimi R, Kauppinen T, Calosing C, Kim JY, Hsieh CL, et al. Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. J Neurosci 2015, 35: 3384–3396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Davies MA. The role of the PI3K-AKT pathway in melanoma. Cancer J 2012, 18: 142–147.

    Article  CAS  PubMed  Google Scholar 

  13. Kretz A, Happold CJ, Marticke JK, Isenmann S. Erythropoietin promotes regeneration of adult CNS neurons via Jak2/Stat3 and PI3K/AKT pathway activation. Mol Cell Neurosci 2005, 29: 569–579.

    Article  CAS  PubMed  Google Scholar 

  14. Zhu M, Li D, Wu Y, Huang X, Wu M. TREM-2 promotes macrophage-mediated eradication of Pseudomonas aeruginosa via a PI3K/Akt pathway. Scand J Immunol 2014, 79: 187–196.

    Article  CAS  PubMed  Google Scholar 

  15. Slenter DN, Kutmon M, Hanspers K, Riutta A, Windsor J, Nunes N, et al. WikiPathways: a multifaceted pathway database bridging metabolomics to other omics research. Nucleic Acids Res 2018, 46: D661–D667.

    Article  CAS  PubMed  Google Scholar 

  16. Xie N, Wang C, Wu C, Cheng X, Gao Y, Zhang H, et al. Mdivi-1 protects epileptic hippocampal neurons from apoptosis via inhibiting oxidative stress and endoplasmic reticulum stress in vitro. Neurochem Res 2016, 41: 1335–1342.

    Article  CAS  PubMed  Google Scholar 

  17. Whalley BJ, Stephens GJ, Constanti A. Investigation of the effects of the novel anticonvulsant compound carisbamate (RWJ-333369) on rat piriform cortical neurones in vitro. Br J Pharmacol 2009, 156: 994–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Theofilas P, Brar S, Stewart KA, Shen HY, Sandau US, Poulsen D, et al. Adenosine kinase as a target for therapeutic antisense strategies in epilepsy. Epilepsia 2011, 52: 589–601.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Tao H, Zhao J, Liu T, Cai Y, Zhou X, Xing H, et al. Intranasal delivery of miR-146a mimics delayed seizure onset in the lithium-pilocarpine mouse model. Mediators Inflamm 2017, 2017: 6512620.

    PubMed  PubMed Central  Google Scholar 

  20. Ma DL, Qu JQ, Goh EL, Tang FR. Reorganization of basolateral amygdala-subiculum circuitry in mouse epilepsy model. Front Neuroanat 2015, 9: 167.

    PubMed  Google Scholar 

  21. Kelkar MG, Thakur B, Derle A, Chatterjee S, Ray P, De A. Tumor suppressor protein p53 exerts negative transcriptional regulation on human sodium iodide symporter gene expression in breast cancer. Breast Cancer Res Treat 2017, 164: 603–615.

    Article  CAS  PubMed  Google Scholar 

  22. Wyatt SK, Witt T, Barbaro NM, Cohen-Gadol AA, Brewster AL. Enhanced classical complement pathway activation and altered phagocytosis signaling molecules in human epilepsy. Exp Neurol 2017, 295: 184–193.

    Article  CAS  PubMed  Google Scholar 

  23. Le Ber I, De Septenville A, Guerreiro R, Bras J, Camuzat A, Caroppo P, et al. Homozygous TREM2 mutation in a family with atypical frontotemporal dementia. Neurobiol Aging 2014, 35: 2419 e2423–2419 e2425.

  24. Wei H, Duan G, He J, Meng Q, Liu Y, Chen W, et al. Geniposide attenuates epilepsy symptoms in a mouse model through the PI3K/Akt/GSK-3beta signaling pathway. Exp Ther Med 2018, 15: 1136–1142.

    CAS  PubMed  Google Scholar 

  25. Guo XQ, Cao YL, Hao F, Yan ZR, Wang ML, Liu XW. Tangeretin alters neuronal apoptosis and ameliorates the severity of seizures in experimental epilepsy-induced rats by modulating apoptotic protein expressions, regulating matrix metalloproteinases, and activating the PI3K/Akt cell survival pathway. Adv Med Sci 2017, 62: 246–253.

    Article  PubMed  Google Scholar 

  26. Xiao Z, Peng J, Gan N, Arafat A, Yin F. Interleukin-1beta plays a pivotal role via the PI3K/Akt/mTOR signaling pathway in the chronicity of mesial temporal lobe epilepsy. Neuroimmunomodulation 2016, 23: 332–344.

    Article  CAS  PubMed  Google Scholar 

  27. Thompson S, Kelly CA, Griffiths ID, Turner GA. Abnormally-fucosylated serum haptoglobins in patients with inflammatory joint disease. Clin Chim Acta 1989, 184: 251–258.

    Article  CAS  PubMed  Google Scholar 

  28. Zhao X, Chen Y, Qiu G, Xiao M, Zhong N. Reducing preterm births in China. Lancet 2012, 380: 1144–1145; author reply 1145.

  29. Wu R, Li X, Xu P, Huang L, Cheng J, Huang X, et al. TREM2 protects against cerebral ischemia/reperfusion injury. Mol Brain 2017, 10: 20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, et al. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem 2009, 109: 1144–1156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ren M, Guo Y, Wei X, Yan S, Qin Y, Zhang X, et al. TREM2 overexpression attenuates neuroinflammation and protects dopaminergic neurons in experimental models of Parkinson’s disease. Exp Neurol 2018, 302: 205–213.

    Article  CAS  PubMed  Google Scholar 

  32. Jiang T, Tan L, Zhu XC, Zhang QQ, Cao L, Tan MS, et al. Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology 2014, 39: 2949–2962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 2007, 4: e124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kleinberger G, Yamanishi Y, Suarez-Calvet M, Czirr E, Lohmann E, Cuyvers E, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 2014, 6: 243ra286.

  35. Ercegovac M, Jovic N, Simic T, Beslac-Bumbasirevic L, Sokic D, Djukic T, et al. Byproducts of protein, lipid and DNA oxidative damage and antioxidant enzyme activities in seizure. Seizure 2010, 19: 205–210.

    Article  PubMed  Google Scholar 

  36. Li J, Wang LN, Xiao HL, Li X, Yang JJ. Effect of electroacupuncture intervention on levels of SOD, GSH, GSH-Px, MDA, and apoptosis of dopaminergic neurons in substantia Nigra in rats with Parkinson’s disease. Zhen Ci Yan Jiu 2014, 39: 185–191.

    Google Scholar 

  37. Kilic U, Caglayan AB, Beker MC, Gunal MY, Caglayan B, Yalcin E, et al. Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin’s neuroprotective activity after focal cerebral ischemia in mice. Redox Biol 2017, 12: 657–665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhuang Z, Zhao X, Wu Y, Huang R, Zhu L, Zhang Y, et al. The anti-apoptotic effect of PI3K-Akt signaling pathway after subarachnoid hemorrhage in rats. Ann Clin Lab Sci 2011, 41: 364–372.

    CAS  PubMed  Google Scholar 

  39. Liu G, Wang T, Wang T, Song J, Zhou Z. Effects of apoptosis-related proteins caspase-3, Bax and Bcl-2 on cerebral ischemia rats. Biomed Rep 2013, 1: 861–867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mao W, Yi X, Qin J, Tian M, Jin G. CXCL12 inhibits cortical neuron apoptosis by increasing the ratio of Bcl-2/Bax after traumatic brain injury. Int J Neurosci 2014, 124: 281–290.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We sincerely appreciate the reviewers’ critical comments on this article. This work was supported by Beijing Key Laboratory of Neuromodulation (BZ0098), the Precision Medicine Project of the Ministry of Science and Technology of China (2016YFC0904400).

Author information

Authors and Affiliations

  1. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China

    Ai-Hua Liu, Min Chu & Yu-Ping Wang

Authors
  1. Ai-Hua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-Ping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu-Ping Wang.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest in this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 51 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, AH., Chu, M. & Wang, YP. Up-Regulation of Trem2 Inhibits Hippocampal Neuronal Apoptosis and Alleviates Oxidative Stress in Epilepsy via the PI3K/Akt Pathway in Mice. Neurosci. Bull. 35, 471–485 (2019). https://doi.org/10.1007/s12264-018-0324-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-018-0324-5

Keywords

Search

Navigation