Skip to main content

Advertisement

SpringerLink
Log in

SOCE-mediated NFAT1–NOX2–NLRP1 inflammasome involves in lipopolysaccharide-induced neuronal damage and Aβ generation

  • Original Article
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The level of lipopolysaccharide (LPS) is higher in the blood and brains of patients with Alzheimer's disease (AD), and this phenomenon is strongly linked to AD-related neuronal damage and β-amyloid (Aβ) generation. However, the mechanism by which LPS causes neuronal damage has still not been fully clarified. Oxidative stress, neuroinflammation, and Ca2+ overload are regarded as important factors influencing AD. NADPH oxidase 2 (NOX2) and the NOD-like receptor family protein 1 (NLRP1) inflammasome play important roles in promoting oxidative stress and inflammation in neurons. Ca2+ overload can activate calcineurin (CN), which further dephosphorylates nuclear factor of activated T cells (NFAT), leading to its translocation into the nucleus to regulate gene transcription. In the present study, LPS (250 µg/kg) exposure for 14 days was used to induce cognitive dysfunction in mice and LPS (20 µg/ml) exposure for 48 h was used to induce neuronal damage in HT22 cells. The results showed that LPS exposure activated phospholipase C (PLC), CN, and NFAT1; increased the expressions of NOX2- and NLRP1-related proteins; and promoted neuronal damage and Aβ deposition in mice and HT22 cells. However, treatment with 2-APB (SOCE inhibitor), apocynin (NOX inhibitor), or tempol (reactive oxygen species scavenger) significantly reversed these LPS-induced changes, and improved neuronal damage and Aβ deposition. Moreover, LPS exposure promoted PLC phosphorylation, increased the level of inositol-1,4,5-triphosphate, elevated the intracellular Ca2+ concentration ([Ca2+]i), and disrupted [Ca2+]i homeostasis in HT22 cells. These data indicated that the activation of SOCE-mediated NFAT1–NOX2–NLRP1 inflammasome involves in LPS-induced neuronal damage and Aβ generation.

Graphical abstract

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
Fig. 9
Fig. 10

Similar content being viewed by others

Data availability

The data from this manuscript are available from the corresponding author upon reasonable request.

Abbreviations

LPS:

Lipopolysaccharide

DAG:

Diacylglycerol

AD:

Alzheimer's disease

NOX2:

NADPH oxidase 2

IP3:

Inositol-1,4,5-triphosphate

SOCC:

Store-operated calcium channels

SOCE:

Store-operated calcium entry

CN:

Calcineurin

NFAT1:

Nuclear factor of activated T cells 1

2-APB:

2-Aminoethyl diphenylborinate

TLR4:

Toll-like receptor 4

PLC:

Phospholipase C

SOD:

Superoxide dismutase

ROS:

Reactive oxygen species

ALS:

Amyotrophic lateral sclerosis

PSD95:

Postsynaptic density protein 95

MWM:

Morris water maze

[Ca2 +]i :

Intracellular Ca2+ concentration

Aβ:

β-Amyloid

IP3R:

Inositol-1,4,5-triphosphate receptor

PIP2:

Phosphatidylinositol bisphosphate

References

  1. Zarifkar A, Choopani S, Ghasemi R, Naghdi N, Maghsoudi AH, Maghsoudi N, Rastegar K, Moosavi M (2010) Agmatine prevents LPS-induced spatial memory impairment and hippocampal apoptosis. Eur J Pharmacol 634(1–3):84–88. https://doi.org/10.1016/j.ejphar.2010.02.029

    Article  CAS  PubMed  Google Scholar 

  2. Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, Hong JT (2008) Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation 5:37. https://doi.org/10.1186/1742-2094-5-37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhao WX, Zhang JH, Cao JB, Wang W, Wang DX, Zhang XY, Yu J, Zhang YY et al (2017) Acetaminophen attenuates lipopolysaccharide-induced cognitive impairment through antioxidant activity. J Neuroinflammation 14(1):17. https://doi.org/10.1186/s12974-016-0781-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang XY, Cao JB, Zhang LM, Li YF, Mi WD (2015) Deferoxamine attenuates lipopolysaccharide-induced neuroinflammation and memory impairment in mice. J Neuroinflammation 12:20. https://doi.org/10.1186/s12974-015-0238-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yang Y, Wandler AM, Postlethwait JH, Guillemin K (2012) Dynamic Evolution of the LPS-Detoxifying Enzyme Intestinal Alkaline Phosphatase in Zebrafish and Other Vertebrates. Front Immunol 3:314. https://doi.org/10.3389/fimmu.2012.00314

    Article  PubMed  PubMed Central  Google Scholar 

  6. Zhan X, Stamova B, Jin LW, DeCarli C, Phinney B, Sharp FR (2016) Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology 87(22):2324–2332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhan X, Stamova B, Sharp FR (2018) Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review. Front Aging Neurosci 10:42. https://doi.org/10.3389/fnagi.2018.00042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang R, Miller RG, Gascon R, Champion S, Katz J, Lancero M, Narvaez A, Honrada R et al (2009) Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol 206(1–2):121–124. https://doi.org/10.1016/j.jneuroim.2008.09.017

    Article  CAS  PubMed  Google Scholar 

  9. Zhan X, Cox C, Ander BP, Liu D, Stamova B, Jin LW, Jickling GC, Sharp FR (2015) Inflammation Combined with Ischemia Produces Myelin Injury and Plaque-Like Aggregates of Myelin, Amyloid-beta and AbetaPP in Adult Rat Brain. J Alzheimers Dis 46(2):507–523. https://doi.org/10.3233/JAD-143072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sun Y, Ge X, Li M, Xu L, Shen Y (2017) Dyrk2 involved in regulating LPS-induced neuronal apoptosis. Int J Biol Macromol 104(Pt A):979–986. https://doi.org/10.1016/j.ijbiomac.2017.06.087

    Article  CAS  PubMed  Google Scholar 

  11. Tarafdar A, Pula G (2018) The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders. Int J Mol Sci 19 (12). https://doi.org/10.3390/ijms19123824

  12. Park L, Anrather J, Girouard H, Zhou P, Iadecola C (2007) Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J Cereb Blood Flow Metab 27(12):1908–1918. https://doi.org/10.1038/sj.jcbfm.9600491

    Article  CAS  PubMed  Google Scholar 

  13. Zhang B, Zhang Y, Xu T, Yin Y, Huang R, Wang Y, Zhang J, Huang D et al (2017) Chronic dexamethasone treatment results in hippocampal neurons injury due to activate NLRP1 inflammasome in vitro. Int Immunopharmacol 49:222–230.

    Article  CAS  PubMed  Google Scholar 

  14. Kaushal V, Dye R, Pakavathkumar P, Foveau B, Flores J, Hyman B, Ghetti B, Koller BH et al (2015) Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell Death Differ 22(10):1676–1686. https://doi.org/10.1038/cdd.2015.16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Masters SL, Gerlic M, Metcalf D, Preston S, Pellegrini M, O’Donnell JA, McArthur K, Baldwin TM et al (2012) NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity 37(6):1009–1023. https://doi.org/10.1016/j.immuni.2012.08.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sun L, Chen Y, Shen X, Xu T, Yin Y, Zhang H, Ding S, Zhao Y et al (2019) Inhibition of NOX2-NLRP1 signaling pathway protects against chronic glucocorticoids exposure-induced hippocampal neuronal damage. Int Immunopharmacol 74:105721 (S1567-5769(19)30374-1)

    Article  CAS  PubMed  Google Scholar 

  17. Xu T, Sun L, Shen X, Chen Y, Yin Y, Zhang J, Huang D, Li W et al (2019) NADPH oxidase 2-mediated NLRP1 inflammasome activation involves in neuronal senescence in hippocampal neurons in vitro. Int Immunopharmacol 69:60–70. https://doi.org/10.1016/j.intimp.2019.01.025

    Article  CAS  PubMed  Google Scholar 

  18. Xu TZ, Shen XY, Sun LL, Chen YL, Zhang BQ, Huang DK, Li WZ (2019) Ginsenoside Rg1 protects against H2O2induced neuronal damage due to inhibition of the NLRP1 inflammasome signalling pathway in hippocampal neurons in vitro. Int J Mol Med 43(2):717–726. https://doi.org/10.3892/ijmm.2018.4005

    Article  CAS  PubMed  Google Scholar 

  19. Muhammad T, Ikram M, Ullah R, Rehman SU, Kim MO (2019) Hesperetin, a Citrus Flavonoid, Attenuates LPS-Induced Neuroinflammation, Apoptosis and Memory Impairments by Modulating TLR4/NF-kappaB Signaling. Nutrients 11(3). https://doi.org/10.3390/nu11030648

  20. d’Avila JC, Siqueira LD, Mazeraud A, Azevedo EP, Foguel D, Castro-Faria-Neto HC, Sharshar T, Chretien F et al (2018) Age-related cognitive impairment is associated with long-term neuroinflammation and oxidative stress in a mouse model of episodic systemic inflammation. J Neuroinflammation 15(1):28. https://doi.org/10.1186/s12974-018-1059-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Qin L, Liu Y, Hong JS, Crews FT (2013) NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration. Glia 61(6):855–868. https://doi.org/10.1002/glia.22479

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chakroborty S, Stutzmann GE (2011) Early calcium dysregulation in Alzheimer’s disease: setting the stage for synaptic dysfunction. Sci China Life Sci 54(8):752–762. https://doi.org/10.1007/s11427-011-4205-7

    Article  CAS  PubMed  Google Scholar 

  23. Pascual-Caro C, Espinosa-Bermejo N, Pozo-Guisado E, Martin-Romero FJ (2018) Role of STIM1 in neurodegeneration. World J Biol Chem 9(2):16–24. https://doi.org/10.4331/wjbc.v9.i2.16

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bavencoffe A, Zhu MX, Tian JB (2017) New Aspects of the Contribution of ER to SOCE Regulation: TRPC Proteins as a Link Between Plasma Membrane Ion Transport and Intracellular Ca(2+) Stores. Adv Exp Med Biol 993:239–255. https://doi.org/10.1007/978-3-319-57732-6_13

    Article  CAS  PubMed  Google Scholar 

  25. Darbellay B, Arnaudeau S, Konig S, Jousset H, Bader C, Demaurex N, Bernheim L (2009) STIM1- and Orai1-dependent store-operated calcium entry regulates human myoblast differentiation. J Biol Chem 284(8):5370–5380. https://doi.org/10.1074/jbc.M806726200

    Article  CAS  PubMed  Google Scholar 

  26. Wegierski T, Kuznicki J (2018) Neuronal calcium signaling via store-operated channels in health and disease. Cell Calcium 74:102–111.

    Article  CAS  PubMed  Google Scholar 

  27. Calvo-Rodriguez M, Hernando-Perez E, Nunez L, Villalobos C (2019) Amyloid beta Oligomers Increase ER-Mitochondria Ca(2+) Cross Talk in Young Hippocampal Neurons and Exacerbate Aging-Induced Intracellular Ca(2+) Remodeling. Front Cell Neurosci 13:22. https://doi.org/10.3389/fncel.2019.00022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chandran R, Kumar M, Kesavan L, Jacob RS, Gunasekaran S, Lakshmi S, Sadasivan C, Omkumar RV (2019) Cellular calcium signaling in the aging brain. J Chem Neuroanat 95:95–114. https://doi.org/10.1016/j.jchemneu.2017.11.008

    Article  CAS  PubMed  Google Scholar 

  29. He RL, Wu ZJ, Liu XR, Gui LX, Wang RX, Lin MJ (2018) Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats. Cell Physiol Biochem 49(1):172–189. https://doi.org/10.1159/000492852

    Article  CAS  PubMed  Google Scholar 

  30. Foster TC, Sharrow KM, Masse JR, Norris CM, Kumar A (2001) Calcineurin links Ca2+ dysregulation with brain aging. J Neurosci 21(11):4066–4073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Foster TC, Norris CM (1997) Age-associated changes in Ca(2+)-dependent processes: relation to hippocampal synaptic plasticity. Hippocampus 7(6):602–612. https://doi.org/10.1002/(SICI)1098-1063(1997)7:6%3c602::AID-HIPO3%3e3.0.CO;2-G

    Article  CAS  PubMed  Google Scholar 

  32. Quang CT, Leboucher S, Passaro D, Fuhrmann L, Nourieh M, Vincent-Salomon A, Ghysdael J (2015) The calcineurin/NFAT pathway is activated in diagnostic breast cancer cases and is essential to survival and metastasis of mammary cancer cells. Cell Death Dis 6:e1658. https://doi.org/10.1038/cddis.2015.14

    Article  CAS  PubMed  Google Scholar 

  33. Abdul HM, Sama MA, Furman JL, Mathis DM, Beckett TL, Weidner AM, Patel ES, Baig I et al (2009) Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci 29(41):12957–12969. https://doi.org/10.1523/JNEUROSCI.1064-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Calvo-Rodriguez M, de la Fuente C, Garcia-Durillo M, Garcia-Rodriguez C, Villalobos C, Nunez L (2017) Aging and amyloid beta oligomers enhance TLR4 expression, LPS-induced Ca(2+) responses, and neuron cell death in cultured rat hippocampal neurons. J Neuroinflammation 14(1):24. https://doi.org/10.1186/s12974-017-0802-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Boutajangout A, Lindberg H, Awwad A, Paul A, Baitalmal R, Almokyad I, Hoiden-Guthenberg I, Gunneriusson E et al (2019) Affibody-Mediated Sequestration of Amyloid beta Demonstrates Preventive Efficacy in a Transgenic Alzheimer’s Disease Mouse Model. Front Aging Neurosci 11:64. https://doi.org/10.3389/fnagi.2019.00064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhao Y, Jaber V, Lukiw WJ (2017) Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer’s Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus. Front Cell Infect Microbiol 7:318. https://doi.org/10.3389/fcimb.2017.00318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhou J, Yu W, Zhang M, Tian X, Li Y, Lu Y (2019) Imbalance of Microglial TLR4/TREM2 in LPS-Treated APP/PS1 Transgenic Mice: A Potential Link Between Alzheimer’s Disease and Systemic Inflammation. Neurochem Res 44(5):1138–1151. https://doi.org/10.1007/s11064-019-02748-x

    Article  CAS  PubMed  Google Scholar 

  38. Liu Y, Zhang Y, Zheng X, Fang T, Yang X, Luo X, Guo A, Newell KA et al (2018) Galantamine improves cognition, hippocampal inflammation, and synaptic plasticity impairments induced by lipopolysaccharide in mice. J Neuroinflammation 15(1):112. https://doi.org/10.1186/s12974-018-1141-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368(9533):387–403. https://doi.org/10.1016/S0140-6736(06)69113-7

    Article  CAS  PubMed  Google Scholar 

  40. De Strooper B, Karran E (2016) The Cellular Phase of Alzheimer’s Disease. Cell 164(4):603–615. https://doi.org/10.1016/j.cell.2015.12.056

    Article  CAS  PubMed  Google Scholar 

  41. Badshah H, Ali T, Kim MO (2016) Osmotin attenuates LPS-induced neuroinflammation and memory impairments via the TLR4/NFkappaB signaling pathway. Sci Rep 6:24493. https://doi.org/10.1038/srep24493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Selkoe DJ (1998) The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol 8(11):447–453. https://doi.org/10.1016/s0962-8924(98)01363-4

    Article  CAS  PubMed  Google Scholar 

  43. Jin WS, Shen LL, Bu XL, Zhang WW, Chen SH, Huang ZL, Xiong JX, Gao CY et al (2017) Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model. Acta Neuropathol 134(2):207–220. https://doi.org/10.1007/s00401-017-1721-y

    Article  CAS  PubMed  Google Scholar 

  44. Choi SI, Lee B, Woo JH, Jeong JB, Jun I, Kim EK (2019) APP processing and metabolism in corneal fibroblasts and epithelium as a potential biomarker for Alzheimer’s disease. Exp Eye Res 182:167–174. https://doi.org/10.1016/j.exer.2019.03.012

    Article  CAS  PubMed  Google Scholar 

  45. Al-Atrache Z, Lopez DB, Hingley ST, Appelt DM (2019) Astrocytes infected with Chlamydia pneumoniae demonstrate altered expression and activity of secretases involved in the generation of beta-amyloid found in Alzheimer disease. BMC Neurosci 20(1):6. https://doi.org/10.1186/s12868-019-0489-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fischer R, Maier O (2015) Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev 2015:610813. https://doi.org/10.1155/2015/610813

    Article  PubMed  PubMed Central  Google Scholar 

  47. Magi S, Castaldo P, Macri ML, Maiolino M, Matteucci A, Bastioli G, Gratteri S, Amoroso S et al (2016) Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease. Biomed Res Int 2016:6701324. https://doi.org/10.1155/2016/6701324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Taupin P (2010) A dual activity of ROS and oxidative stress on adult neurogenesis and Alzheimer’s disease. Cent Nerv Syst Agents Med Chem 10(1):16–21. https://doi.org/10.2174/187152410790780172

    Article  CAS  PubMed  Google Scholar 

  49. Shah SA, Khan M, Jo MH, Jo MG, Amin FU, Kim MO (2017) Melatonin Stimulates the SIRT1/Nrf2 Signaling Pathway Counteracting Lipopolysaccharide (LPS)-Induced Oxidative Stress to Rescue Postnatal Rat Brain. CNS Neurosci Ther 23(1):33–44. https://doi.org/10.1111/cns.12588

    Article  CAS  PubMed  Google Scholar 

  50. Quick KL, Ali SS, Arch R, Xiong C, Wozniak D, Dugan LL (2008) A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice. Neurobiol Aging 29(1):117–128. https://doi.org/10.1016/j.neurobiolaging.2006.09.014

    Article  CAS  PubMed  Google Scholar 

  51. Dugan LL, Ali SS, Shekhtman G, Roberts AJ, Lucero J, Quick KL, Behrens MM (2009) IL-6 mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase. PLoS ONE 4(5):e5518. https://doi.org/10.1371/journal.pone.0005518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cahill-Smith S, Li JM (2014) Oxidative stress, redox signalling and endothelial dysfunction in ageing-related neurodegenerative diseases: a role of NADPH oxidase 2. Br J Clin Pharmacol 78(3):441–453. https://doi.org/10.1111/bcp.12357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ali SS, Young JW, Wallace CK, Gresack J, Jeste DV, Geyer MA, Dugan LL, Risbrough VB (2011) Initial evidence linking synaptic superoxide production with poor short-term memory in aged mice. Brain Res 1368:65–70. https://doi.org/10.1016/j.brainres.2010.11.009

    Article  CAS  PubMed  Google Scholar 

  54. Tammariello SP, Quinn MT, Estus S (2000) NADPH oxidase contributes directly to oxidative stress and apoptosis in nerve growth factor-deprived sympathetic neurons. J Neurosci 20(1):RC53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245–313.

    Article  CAS  PubMed  Google Scholar 

  56. Liu L, Chan C (2014) The role of inflammasome in Alzheimer’s disease. Ageing Res Rev 15:6–15. https://doi.org/10.1016/j.arr.2013.12.007

    Article  CAS  PubMed  Google Scholar 

  57. Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2(1):a006346. https://doi.org/10.1101/cshperspect.a006346

    Article  PubMed  PubMed Central  Google Scholar 

  58. Venegas C, Heneka MT (2019) Inflammasome-mediated innate immunity in Alzheimer’s disease. FASEB J 33(12):13075–13084. https://doi.org/10.1096/fj.201900439

    Article  CAS  PubMed  Google Scholar 

  59. Man SM, Kanneganti TD (2015) Regulation of inflammasome activation. Immunol Rev 265(1):6–21. https://doi.org/10.1111/imr.12296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Arioz BI, Tastan B, Tarakcioglu E, Tufekci KU, Olcum M, Ersoy N, Bagriyanik A, Genc K et al (2019) Melatonin Attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 Inflammasome Activation Through the SIRT1/Nrf2 Pathway. Front Immunol 10:1511. https://doi.org/10.3389/fimmu.2019.01511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang Q, Zhao S, Zheng W, Fu H, Wu T, Hu F (2020) Plumbagin attenuated oxygen-glucose deprivation/reoxygenation-induced injury in human SH-SY5Y cells by inhibiting NOX4-derived ROS-activated NLRP3 inflammasome. Biosci Biotechnol Biochem 84(1):134–142. https://doi.org/10.1080/09168451.2019.1664893

    Article  CAS  PubMed  Google Scholar 

  62. Mamik MK, Power C (2017) Inflammasomes in neurological diseases: emerging pathogenic and therapeutic concepts. Brain 140(9):2273–2285. https://doi.org/10.1093/brain/awx133

    Article  PubMed  Google Scholar 

  63. Ma C, Li S, Hu Y, Ma Y, Wu Y, Wu C, Liu X, Wang B, Hu G, Zhou J, Yang S (2021) AIM2 controls microglial inflammation to prevent experimental autoimmune encephalomyelitis. J Exp Med 218(5). https://doi.org/10.1084/jem.20201796

  64. Zhang F, Jiang L (2015) Neuroinflammation in Alzheimer’s disease. Neuropsychiatr Dis Treat 11:243–256. https://doi.org/10.2147/NDT.S75546

    Article  PubMed  PubMed Central  Google Scholar 

  65. Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Heneka MT (2003) Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci 23(30):9796–9804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ehrenmann M, Tomakidi P, Hellwig E, Schulz SD, Polydorou O (2017) Effects of low-dose Bisphenol A on calcium ion influx and on genes of proliferation and differentiation in immortalized human gingival cells in vitro: The role of estrogen receptor beta. Dent Mater 33(9):1021–1032.

    Article  CAS  PubMed  Google Scholar 

  67. Tojima T, Hines JH, Henley JR, Kamiguchi H (2011) Second messengers and membrane trafficking direct and organize growth cone steering. Nat Rev Neurosci 12(4):191–203. https://doi.org/10.1038/nrn2996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Berridge MJ (2010) Calcium hypothesis of Alzheimer’s disease. Pflugers Arch 459(3):441–449. https://doi.org/10.1007/s00424-009-0736-1

    Article  CAS  PubMed  Google Scholar 

  69. Bezprozvanny I (2009) Calcium signaling and neurodegenerative diseases. Trends Mol Med 15(3):89–100. https://doi.org/10.1016/j.molmed.2009.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mattson MP (2007) Calcium and neurodegeneration. Aging Cell 6(3):337–350. https://doi.org/10.1111/j.1474-9726.2007.00275.x

    Article  CAS  PubMed  Google Scholar 

  71. Avila-Medina J, Calderon-Sanchez E, Gonzalez-Rodriguez P, Monje-Quiroga F, Rosado JA, Castellano A, Ordonez A, Smani T (2016) Orai1 and TRPC1 Proteins Co-localize with CaV1.2 Channels to Form a Signal Complex in Vascular Smooth Muscle Cells. J Biol Chem 291(40):21148–21159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Beziau DM, Toussaint F, Blanchette A, Dayeh NR, Charbel C, Tardif JC, Dupuis J, Ledoux J (2015) Expression of phosphoinositide-specific phospholipase C isoforms in native endothelial cells. PLoS ONE 10(4):e0123769. https://doi.org/10.1371/journal.pone.0123769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jiao FZ, Wang Y, Zhang HY, Zhang WB, Wang LW, Gong ZJ (2018) Histone Deacetylase 2 Inhibitor CAY10683 Alleviates Lipopolysaccharide Induced Neuroinflammation Through Attenuating TLR4/NF-kappaB Signaling Pathway. Neurochem Res 43(6):1161–1170. https://doi.org/10.1007/s11064-018-2532-9

    Article  CAS  PubMed  Google Scholar 

  74. Zhao C, Hou W, Lei H, Huang L, Wang S, Cui D, Xing C, Wang X et al (2017) Potassium 2-(l-hydroxypentyl)-benzoate attenuates neuroinflammatory responses and upregulates heme oxygenase-1 in systemic lipopolysaccharide-induced inflammation in mice. Acta Pharm Sin B 7(4):470–478. https://doi.org/10.1016/j.apsb.2017.04.007

    Article  PubMed  PubMed Central  Google Scholar 

  75. Bittremieux M, Gerasimenko JV, Schuermans M, Luyten T, Stapleton E, Alzayady KJ, De Smedt H, Yule DI et al (2017) DPB162-AE, an inhibitor of store-operated Ca(2+) entry, can deplete the endoplasmic reticulum Ca(2+) store. Cell Calcium 62:60–70. https://doi.org/10.1016/j.ceca.2017.01.015

    Article  CAS  PubMed  Google Scholar 

  76. Furman JL, Sompol P, Kraner SD, Pleiss MM, Putman EJ, Dunkerson J, Mohmmad Abdul H, Roberts KN et al (2016) Blockade of Astrocytic Calcineurin/NFAT Signaling Helps to Normalize Hippocampal Synaptic Function and Plasticity in a Rat Model of Traumatic Brain Injury. J Neurosci 36(5):1502–1515. https://doi.org/10.1523/JNEUROSCI.1930-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rajput MS, Nirmal NP, Rathore D, Dahima R (2020) Dimethyl fumarate exerts neuroprotection by modulating calcineurin/NFAT1 and NFkappaB dependent BACE1 activity in Abeta1-42 treated neuroblastoma SH-SY5Y cells. Brain Res Bull 165:97–107. https://doi.org/10.1016/j.brainresbull.2020.08.024

    Article  CAS  PubMed  Google Scholar 

  78. Thapak P, Khare P, Bishnoi M, Sharma SS (2020) Neuroprotective Effect of 2-Aminoethoxydiphenyl Borate (2-APB) in Amyloid beta-Induced Memory Dysfunction: A Mechanistic Study. Cell Mol Neurobiol. https://doi.org/10.1007/s10571-020-01012-z

    Article  PubMed  Google Scholar 

  79. Hou L, Sun F, Huang R, Sun W, Zhang D, Wang Q (2019) Inhibition of NADPH oxidase by apocynin prevents learning and memory deficits in a mouse Parkinson’s disease model. Redox Biol 22:101134. https://doi.org/10.1016/j.redox.2019.101134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Joseph E, Villalobos-Acosta DMA, Torres-Ramos MA, Farfan-Garcia ED, Gomez-Lopez M, Miliar-Garcia A, Fragoso-Vazquez MJ, Garcia-Marin ID et al (2020) Neuroprotective Effects of Apocynin and Galantamine During the Chronic Administration of Scopolamine in an Alzheimer’s Disease Model. J Mol Neurosci 70(2):180–193. https://doi.org/10.1007/s12031-019-01426-5

    Article  CAS  PubMed  Google Scholar 

  81. Chiarotto GB, Cartarozzi LP, Perez M, Biscola NP, Spejo AB, Gubert F, Franca Junior M, Mendez-Otero R et al (2019) Tempol improves neuroinflammation and delays motor dysfunction in a mouse model (SOD1(G93A)) of ALS. J Neuroinflammation 16(1):218. https://doi.org/10.1186/s12974-019-1598-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chonpathompikunlert P, Han J, Toh K, Isoda H, Nagasaki Y (2011) TEMPOL protects human neuroblastoma SH-SY5Y cells against beta-amyloid-induced cell toxicity. Eur J Pharmacol 650(2–3):544–549. https://doi.org/10.1016/j.ejphar.2010.10.028

    Article  CAS  PubMed  Google Scholar 

  83. Dohare P, Hyzinski-Garcia MC, Vipani A, Bowens NH, Nalwalk JW, Feustel PJ, Keller RW Jr, Jourd’heuil D et al (2014) The neuroprotective properties of the superoxide dismutase mimetic tempol correlate with its ability to reduce pathological glutamate release in a rodent model of stroke. Free Radic Biol Med 77:168–182. https://doi.org/10.1016/j.freeradbiomed.2014.08.029

    Article  CAS  PubMed  Google Scholar 

  84. Zheng J, Fang F, Zeng X, Medler TR, Fiorillo AA, Clevenger CV (2011) Negative cross talk between NFAT1 and Stat5 signaling in breast cancer. Mol Endocrinol 25(12):2054–2064. https://doi.org/10.1210/me.2011-1141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gorlach A, Bertram K, Hudecova S, Krizanova O (2015) Calcium and ROS: A mutual interplay. Redox Biol 6:260–271. https://doi.org/10.1016/j.redox.2015.08.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Madreiter-Sokolowski CT, Thomas C, Ristow M (2020) Interrelation between ROS and Ca(2+) in aging and age-related diseases. Redox Biol 36:101678. https://doi.org/10.1016/j.redox.2020.101678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank Zhirui Fang in the Department of Pharmacology and Dake Huang in the Synthetic Laboratory of Basic Medicine College for their technical assistance.

Funding

This study was supported by the Major projects of Anhui Provincial Department of Education (KJ2020ZD14), the National Natural Science Foundation of China (81970630, 81671384) and Basic and Clinical Cooperative Research Promotion Program of Anhui Medical University (2019xkjT021).

Author information

Author notes

  1. Zhenghao Sun and Xuewang Li contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-Inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, Anhui, China

    Zhenghao Sun, Xuewang Li, Liu Yang, Xianan Dong, Yuli Han, Yan Li & Weizu Li

  2. Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China

    Jing Luo

Authors
  1. Zhenghao Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuewang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xianan Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuli Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weizu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Z.S. performed the experiment, analyzed the data, and prepared the manuscript. X.L. and L.Y. performed the behavior test and collected the data. X.D., Y.H., and Y.L. helped to complete the experiment. J.L. and W.L. designed and directed the study and revised the manuscript.

Corresponding author

Correspondence to Weizu Li.

Ethics declarations

Ethics approval

All experimental procedures were approved by the Ethics Committee for Experimental Animal Use and Care of Anhui Medical University.

Competing interests

The authors report no competing interests.

Consent to Participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Figure S1 The process of animal experiment (JPG 239 KB)

12035_2021_2717_MOESM2_ESM.jpg

Supplementary Figure S2 The effects of 2-APB,apocynin and tempol treatment on apoptosis-related proteins in LPS-induced mice(Western blot). (A) The bands of Bax, cleaved-caspase-3 and Bcl-2 inhippocampus tissues; (B-D) The relative expressions of Bax, cleaved-caspase-3and Bcl-2. The data are expressed as mean ± SD, n = 4, **P<0.01compared with LPS group (JPG 487 KB)

12035_2021_2717_MOESM3_ESM.jpg

Supplementary Figure S3 LPS exposureincreases the level of ROS production in HT22 cells (DCFH-DA staining, 200×).(A) The effect of LPS (5, 10, 20 and 40 μg/ml) on ROS generation. (B) Theeffect of 2-APB, apocynin and tempol treatment on ROS generation in LPS-inducedHT22 cells. (C) Quantitative analysis of different doses of LPS on ROSgeneration. (D) Quantitative analysis of 2-APB, apocynin and tempol treatmenton ROS generation. The data are expressed as mean ± SD, n = 3, *P<0.05,**P<0.01 compared with control or LPS group (JPG 1922 KB)

12035_2021_2717_MOESM4_ESM.jpg

Supplementary Figure S4 Chronic LPS exposureincreases the expressions of NOX2 and NLRP1-related mRNAs in HT22 cells(q-PCR). (A-F) The relative mRNA levels of NOX2, p22phox, p47phox, NLRP1,caspase-1 and ASC in HT22 cells. The data are expressed as mean ± SD, n = 3, *P<0.05,**P<0.01 compared with LPS group (JPG 297 KB)

12035_2021_2717_MOESM5_ESM.jpg

Supplementary Figure S5 LPS increased IP3generation and the level of p-PLC in HT22 cells. (A) The levels of IP3 in HT22cells after LPS (20μg/ml) treatment for 5 min, 20 min and 48 h (ELISA, n = 3).(B) The bands of p-PLC and PLC after LPS (20μg/ml) treatment for 5 min, 20 minand 48 h (Western blot, n = 3). (C and D) The relative expressions of PLC andp-PLC. The data are expressed as mean ± SD, no significant (ns), *P<0.05,**P<0.01 compared with control group (JPG 451 KB)

12035_2021_2717_MOESM6_ESM.jpg

Supplementary Figure S6 VIVIT treatment decreases theexpressions of NFAT1, NLRP1 and NOX2 in LPS-induced HT22 cells (Western blot). (A) The bands of NFAT1, NLRP1and NOX2 in HT22 cells; (B-D) The relative expressions of NFAT1, NLRP1 andNOX2. The data are expressed as mean ± SD, n = 3, *P<0.05, **P<0.01 compared with LPS group (JPG 424 KB)

12035_2021_2717_MOESM7_ESM.jpg

Supplementary Figure S7 Chronic LPS exposureincreases the levels of NLRP3, NLRC4 and AIM2 in hippocampus tissues in mice(Western blot). (A) The bands of NLRP3, NLRC4 and AIM2 in hippocampus tissues;(B-D) The relative expressions of NLRP3, NLRC4 and AIM2. The data are expressed as mean ± SD, n = 4, *P<0.05, **P<0.01 compared with LPS group (JPG 576 KB)

Supplementary Table S1 (DOCX 13 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, Z., Li, X., Yang, L. et al. SOCE-mediated NFAT1–NOX2–NLRP1 inflammasome involves in lipopolysaccharide-induced neuronal damage and Aβ generation. Mol Neurobiol 59, 3183–3205 (2022). https://doi.org/10.1007/s12035-021-02717-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-021-02717-y

Keywords

Search

Navigation