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Activation of NLRP3 inflammasome in a rat model of cerebral small vessel disease

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Abstract

Cerebral small vessel disease (CSVD) is increasingly being recognized as a leading contributor to cognitive impairment in the elderly. However, there is a lack of effective preventative or therapeutic options for CSVD. In this exploratory study, we investigated the interplay between neuroinflammation and CSVD pathogenesis as well as the cognitive performance, focusing on NLRP3 signaling as a new therapeutic target. Spontaneously hypertensive stroke-prone (SHRSP) rats served as a CSVD model. We found that SHRSP rats showed decline in learning and memory abilities using morris water maze test. Activated NLRP3 signaling and an increased expression of the downstream pro-inflammatory factors, including IL (interleukin)-6 and tumor necrosis factor α were determined. We also observed a remarkable increase in the production of pyroptosis executive protein gasdermin D, and elevated astrocytic and microglial activation. In addition, we identify several neuropathological hallmarks of CSVD, including blood-brain barrier breakdown, white matter damage, and endothelial dysfunction. These results were in correlation with the activation of NLRP3 inflammasome. Thus, our findings reveal that the NLRP3-mediated inflammatory pathway could play a central role in the pathogenesis of CSVD, presenting a novel target for potential CSVD treatment.

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The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding authors.

References

  • Albornoz EA, Amarilla AA, Modhiran N, Parker S, LI XX, Wijesundara DK, Aguado J, Zamora AP, Mcmillan CLD, Liang B, Peng NYG, Saima SNGJDJ, Fung FT, Lee JN, Paramitha JD, Parry D, Avumegah R, Isaacs MS, Miranda-Chacon ALOMW, Bradshaw Z, Salinas-Rebolledo D, Rajapakse C, Wolvetang NW, Munro EJ, Rojas-Fernandez TP, Young A, Stacey PR, Khromykh KJ, Chappell AA, Watterson KJ, D., Woodruff TM (2022) SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein. Mol Psychiatry

  • Dominic A, Le NT, Takahashi M (2022) Loop between NLRP3 inflammasome and reactive oxygen species. Antioxid Redox Signal 36:784–796

    Article  CAS  PubMed  Google Scholar 

  • Dunn PJ, Harvey NR, Maksemous N, Smith RA, Sutherland HG, Haupt LM, Griffiths LR (2022) Investigation of mitochondrial related variants in a cerebral small Vessel Disease Cohort. Mol Neurobiol 59:5366–5378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edison P (2021) Microglial activation and blood-brain barrier leakage: chicken and egg? Brain 144:1284–1285

    Article  PubMed  PubMed Central  Google Scholar 

  • Gao F, Jing Y, Zang P, Hu X, Gu C, Wu R, Chai B, Zhang Y (2019) Vascular cognitive impairment caused by Cerebral Small Vessel Disease is Associated with the TLR4 in the Hippocampus. J Alzheimers Dis 70:563–572

    Article  PubMed  Google Scholar 

  • Gao Y, Li D, Lin J, Thomas AM, Miao J, Chen D, Li S, Chu C (2022) Cerebral small vessel disease: pathological mechanisms and potential therapeutic targets. Front Aging Neurosci 14:961661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, Robertson AAB, Butler MS, Rowe DB, O’neill LA, Kanthasamy AG, Schroder K, Cooper MA, Woodruff TM (2018) Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med, 10

  • Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Ladecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S, American Heart Association Stroke Council, C. O. E., Prevention, C. O. C. N. C. O. C. R., Intervention, Council on Cardiovascular, S., Anesthesia (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke, 42, 2672 – 713

  • Hainsworth AH, Markus HS (2008) Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review. J Cereb Blood Flow Metab 28:1877–1891

    Article  PubMed  Google Scholar 

  • Hannawi Y, Caceres E, Ewees MG, Powell KA, Bratasz A, Schwab JM, Rink CL, Zweier JL (2021) Characterizing the neuroimaging and histopathological correlates of Cerebral Small Vessel Disease in spontaneously hypertensive stroke-prone rats. Front Neurol 12:740298

    Article  PubMed  PubMed Central  Google Scholar 

  • He X, Yang W, Zeng Z, Wei Y, Gao J, Zhang B, Li L, Liu L, Wan Y, Zeng Q, GONG Z, Liu L, Zhang H, Li Y, Yang S, Hu T, Wu L, Masliah E, Huang S, Cao H (2020) NLRP3-dependent pyroptosis is required for HIV-1 gp120-induced neuropathology. Cell Mol Immunol 17:283–299

    Article  CAS  PubMed  Google Scholar 

  • Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678

    Article  CAS  PubMed  Google Scholar 

  • Heneka MT, Mcmanus RM, Latz E (2018) Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci 19:610–621

    Article  CAS  PubMed  Google Scholar 

  • Henning EC, Warach S, Spatz M (2010) Hypertension-induced vascular remodeling contributes to reduced cerebral perfusion and the development of spontaneous stroke in aged SHRSP rats. J Cereb Blood Flow Metab 30:827–836

    Article  PubMed  Google Scholar 

  • Horie R, Yamori Y, Handa H (1978) An essential difference between stroke-prone SHR (SHRSP) and stroke-resistant SHR (SHRSR). Quantitative evidence obtained by Yamori’s preparation II. Jpn Heart J 19:630–632

    Article  CAS  PubMed  Google Scholar 

  • Hu X, Yan J, Huang L, Araujo C, Peng J, Gao L, Liu S, Tang J, Zuo G, Zhang JH (2021) INT-777 attenuates NLRP3-ASC inflammasome-mediated neuroinflammation via TGR5/cAMP/PKA signaling pathway after subarachnoid hemorrhage in rats. Brain Behav Immun 91:587–600

    Article  CAS  PubMed  Google Scholar 

  • Jalal FY, Yang Y, Thompson JF, Roitbak T, Rosenberg GA (2015) Hypoxia-induced neuroinflammatory white-matter injury reduced by minocycline in SHR/SP. J Cereb Blood Flow Metab 35:1145–1153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaiser D, Weise G, Moller K, Scheibe J, Posel C, Baasch S, Gawlitza M, Lobsien D, Diederich K, Minnerup J, Kranz A, Boltze J, Wagner DC (2014) Spontaneous white matter damage, cognitive decline and neuroinflammation in middle-aged hypertensive rats: an animal model of early-stage cerebral small vessel disease. Acta Neuropathol Commun 2:169

    Article  PubMed  PubMed Central  Google Scholar 

  • Kapasi A, Decarli C, Schneider JA (2017) Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol 134:171–186

    Article  PubMed  PubMed Central  Google Scholar 

  • Kerkhofs D, Van Hagen BT, Milanova IV, Schell KJ, Van Essen H, Wijnands E, Goossens P, Blankesteijn WM, Unger T, Prickaerts J, Biessen EA, Van Oostenbrugge RJ, Foulquier S (2020) Pharmacological depletion of microglia and perivascular macrophages prevents vascular cognitive impairment in Ang II-induced hypertension. Theranostics 10:9512–9527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu T, Zhang L, Joo D, Sun SC (2017) NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2:17023

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu N, Xue Y, Tang J, Zhang M, Ren X, Fu J (2021) The dynamic change of phenotypic markers of smooth muscle cells in an animal model of cerebral small vessel disease. Microvasc Res 133:104061

    Article  CAS  PubMed  Google Scholar 

  • Low A, Mak E, Rowe JB, Markus HS, O’brien JT (2019) Inflammation and cerebral small vessel disease: a systematic review. Ageing Res Rev 53:100916

    Article  CAS  PubMed  Google Scholar 

  • Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E (2018) Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov 17:688

    Article  CAS  PubMed  Google Scholar 

  • Mullard A (2019) NLRP3 inhibitors stoke anti-inflammatory ambitions. Nat Rev Drug Discov 18:405–407

    Article  CAS  PubMed  Google Scholar 

  • Nabika T, Ohara H, Kato N, Isomura M (2012) The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies? Hypertens Res 35:477–484

    Article  CAS  PubMed  Google Scholar 

  • Naeem A, Prakash R, Kumari N, Ali Khan M, Quaiyoom Khan A, Uddin S, Verma S, Robertson AB, Boltze A, J., Shadab Raza S (2024) MCC950 reduces autophagy and improves cognitive function by inhibiting NLRP3-dependent neuroinflammation in a rat model of Alzheimer’s disease. Brain Behav Immun 116:70–84

    Article  CAS  PubMed  Google Scholar 

  • Okamoto K, Aoki K (1963) Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27:282–293

    Article  CAS  PubMed  Google Scholar 

  • Quick S, Moss J, Rajani RM, Williams A (2021) A vessel for change: endothelial dysfunction in Cerebral Small Vessel Disease. Trends Neurosci 44:289–305

    Article  CAS  PubMed  Google Scholar 

  • Rajani RM, Quick S, Ruigrok SR, Graham D, Harris SE, Verhaaren BFJ, FORNAGE M, Dominiczak Seshadrisatanurss, Wardlaw Afsmithc, J. M., Williams A (2018) Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. Sci Transl Med, 10

  • Sharma B, Satija G, Madan A, Garg M, Alam MM, Shaquiquzzaman M, Khanna S, Tiwari P, Parvez S, Iqubal A, Haque SE, Khan MA (2023) Role of NLRP3 inflammasome and its inhibitors as emerging therapeutic drug candidate for Alzheimer’s Disease: a review of mechanism of activation, regulation, and inhibition. Inflammation 46:56–87

    Article  CAS  PubMed  Google Scholar 

  • Shaul PW (2002) Regulation of endothelial nitric oxide synthase: location, location, location. Annu Rev Physiol 64:749–774

    Article  CAS  PubMed  Google Scholar 

  • Swanson KV, Deng M, Ting JP (2019) The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19:477–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang J, Cheng Q, Zhang Y, Hong C, Liu J, Liu X, Chang J (2023) PARP16-Mediated stabilization of amyloid precursor protein mRNA exacerbates Alzheimer’s Disease Pathogenesis. Aging Dis 14:1458–1471

    PubMed  PubMed Central  Google Scholar 

  • Wardlaw JM, Smith C, Dichgans M (2013a) Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 12:483–497

    Article  PubMed  Google Scholar 

  • Wardlaw JM, Smith C, Dichgans M (2019) Small vessel disease: mechanisms and clinical implications. Lancet Neurol 18:684–696

    Article  PubMed  Google Scholar 

  • Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O’brien JT, Barkhof F, Benavente OR, Black SE, Brayne C, Breteler M, Chabriat H, Decarli C, De Leeuw FE, Doubal F, Duering M, Fox NC, Greenberg S, Hachinski V, Kilimann I, Mok V, Oostenbrugge R, Pantoni L, Speck O, Stephan BC, Teipel S, Viswanathan A, Werring D, Chen C, Smith C, Van BUCHEM, Norrving M, Gorelick B, Dichgans PB, M., Neuroimaging ST F. R. V. C. O. 2013b. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol, 12, 822–838

  • Xu J, Nunez G (2023) The NLRP3 inflammasome: activation and regulation. Trends Biochem Sci 48:331–344

    Article  CAS  PubMed  Google Scholar 

  • Yu E, Mercer J, Bennett M (2012) Mitochondria in vascular disease. Cardiovasc Res 95:173–182

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Zhang Y, Wu R, Gao F, Zang P, Hu X, Gu C (2019) Effect of cerebral small vessel disease on cognitive function and TLR4 expression in hippocampus. J Clin Neurosci 67:210–214

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Dong Z, Song W (2020) NLRP3 inflammasome as a novel therapeutic target for Alzheimer’s disease. Signal Transduct Target Ther 5:37

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (82201626), the Natural Science Foundation of Liaoning Province (2022-MS-442), and the Dalian Municipal Medical Key Specialty Climbing Project (2022ZZ215).

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Author notes

  1. Meiyan Zhang and Xiaoyan Lan contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Neurology, Central Hospital of Dalian University of Technology, Dalian, Liaoning, 116033, P.R. China

    Meiyan Zhang, Xiaoyan Lan, Yue Gao, Yu Zou & Chengyan Chu

  2. Department of Neurology and Psychiatry, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, P.R. China

    Shen Li

  3. Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Yajie Liang, Miroslaw Janowski, Piotr Walczak & Chengyan Chu

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  1. Meiyan Zhang
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Contributions

All authors contributed to the study conception and design. M.Y.Z. and X.Y.L. performed the experiments. M.Y.Z. and C.C. analyzed and interpreted the data. M.Y.Z. and C.C. wrote the first draft of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Chengyan Chu.

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Conflict of interest

P.W. and M.J. are co-owners of Ti-com, LLC and IntraART, LLC. All other authors declare that they have no conflict of interest with respect to the research.

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Communicated by Sreedharan Sajikumar.

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Zhang, M., Lan, X., Gao, Y. et al. Activation of NLRP3 inflammasome in a rat model of cerebral small vessel disease. Exp Brain Res (2024). https://doi.org/10.1007/s00221-024-06824-9

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