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Cited by 40Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeuroscience and Neuropharmacology Research

Involvement of RhoA/ROCK Signaling in Aβ-Induced Chemotaxis, Cytotoxicity and Inflammatory Response of Microglial BV2 Cells

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Zhang, Xiaoxu, Ye, Piao, Wang, Dandan, Liu, Yunsheng, Cao, Lan, Wang, Yancong, Xu, Yuxia, Zhu, Cuiqing·2019·Cellular and Molecular Neurobiology
DOI 10.1007/s10571-019-00668-6PMC PMC11462834
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Abstract

Reactive microglia clustering around amyloid plaques in brain is a histopathological feature of Alzheimer's disease (AD) and reflects the contribution of neuroinflammation in AD pathogenesis. β-Amyloid peptide (Aβ) has been shown to induce a range of microglial responses including chemotaxis, cytotoxicity and inflammation, but the underlying mechanism is poorly understood. Considering the fundamental role of RhoA/ROCK signaling in cell migration and its broad implication in AD and neuroinflammation, we hypothesized that RhoA/ROCK signaling might be involved in Aβ-induced microglial responses. From in vivo mouse models including APP/PS1 transgene and fibrillar Aβ stereotactic injection, we observed the elevated expression level of RhoA in reactive microglia. Through a series in vitro cell migration, cytotoxicity and biochemistry assays, we found that RhoA/ROCK signaling plays an essential role in Aβ-induced responses of microglial BV2 cells. Small molecular agents Fasudil and Y27632 showed prominent beneficial effects, which implies the therapeutic potential of RhoA/ROCK signaling inhibitors in AD treatment.

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  • Increasing evidence indicates that RhoA/ROCK signaling has an important role in microglial activation by regulating microglial migration, phagocytosis, and release of inflammatory factors such as ROS, TNFα, IL-6, IL-1β, and NO.

    “Increasing evidence indicates that RhoA/ROCK signaling has an important role in microglial activation by regulating microglial migration, phagocytosis, and release of inflammatory factors such as ROS, tumor necrosis factor α (TNFα), interleukin-6 (IL-6), IL-1β, and NO [152,153].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [153]

    The Introduction links RhoA/ROCK signaling to microglial phagocytosis, and the section on Aβ-induced chemotaxis reports its role in microglial migration. The neuroinflammation section discusses superoxide production, while the BV2-cell inflammatory-response section reports that ROCK inhibitors suppress IL-1β release. Our copy does not establish regulation of TNFα, IL-6, or NO release, so the full list is not supported; page numbers were not supplied. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • RhoA/ROCK signaling is essential for Aβ-induced chemotaxis, cytotoxicity, and inflammatory response of BV2 microglia, and ROCK inhibition by Fasudil or Y27632 suppresses these inflammatory responses.

    “RhoA/ROCK signaling was found to be essential for Aβ-induced chemotaxis, cytotoxicity, and inflammatory response of BV2 microglia, and ROCK inhibition by Fasudil or Y27632 could efficiently suppress these inflammatory responses [153].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [153]

  • Increased RhoA expression has been reported in reactive microglia in APP/PS1 transgenic and fibrillary Aβ injected mouse models.

    “With respect to microglial activation and neuroinflammation in AD, increased RhoA expression has been reported in reactive microglia in APP/PS1 transgenic and fibrillary Aβ injected mouse models [153].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [153]

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Research works printed but not linked: 40

  1. Alokam R, Singhal S, Srivathsav GS, Garigipati S, Puppala S, Sriram D, Perumal Y (2015) Design of dual inhibitors of ROCK-I and NOX2 as potential leads for the treatment of neuroinflammation associated with various neurological diseases including autism spectrum disorder. Mol Biosyst 11(2):607-617. https :// doi.org/10.1039/c4mb0 0570h · DOI
  2. Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) An English translation of Alzheimer's 1907 paper, 'Uber eine eigenartige Erkankung der Hirnrinde'. Clin Anat 8(6):429-431. https ://doi.org/10.1002/ca.98008 0612 · DOI
  3. Ark M, Ozveren E, Yazici G, Korkmaz B, Buyukafsar K, Arikan O, Kubat H, Songu-Mize E (2004) Effects of HA-1077 and Y-27632, two rho-kinase inhibitors, in the human umbilical artery. Cell Biochem Biophys 41(3):331-342. https ://doi. org/10.1385/CBB:41:3:331 · DOI
  4. Chen TJ, Hung HS, Wang DC, Chen SS (2010) The protective effect of Rho-associated kinase inhibitor on aluminum-induced neurotoxicity in rat cortical neurons. Toxicol Sci 116(1):264-272. https ://doi.org/10.1093/toxsc i/kfq11 4 · DOI
  5. Chen J, Sun Z, Jin M, Tu Y, Wang S, Yang X, Chen Q, Zhang X, Han Y, Pi R (2017a) Inhibition of AGEs/RAGE/Rho/ROCK pathway suppresses non-specific neuroinflammation by regulating BV2 microglial M1/M2 polarization through the NF-kappaB pathway. J Neuroimmunol 305:108-114. https ://doi.org/10.1016/j. jneur oim.2017.02.010 · DOI
  6. Chen J, Yin W, Tu Y, Wang S, Yang X, Chen Q, Zhang X, Han Y, Pi R (2017b) L-F001, a novel multifunctional ROCK inhibitor, suppresses neuroinflammation in vitro and in vivo: Involvement of NF-kappaB inhibition and Nrf2 pathway activation. Eur J Pharmacol 806:1-9. https ://doi.org/10.1016/j.ejpha r.2017.03.025 · DOI
  7. Chodniewicz D, Klemke RL (2004) Guiding cell migration through directed extension and stabilization of pseudopodia. Exp Cell Res 301(1):31-37. https ://doi.org/10.1016/j.yexcr .2004.08.006 · DOI
  8. Ebrahimi T, Rust M, Kaiser SN, Slowik A, Beyer C, Koczulla AR, Schulz JB, Habib P, Bach JP (2018) Alpha1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid beta142-stimulated murine astrocytes. J Neuroinflamm 15(1):282. https ://doi.org/10.1186/s1297 4-018-1319-x · DOI
  9. El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13(4):432-438. https ://doi.org/10.1038/nm155 5 · DOI
  10. Fan Y, Xie L, Chung CY (2017) Signaling pathways controlling microglia chemotaxis. Mol Cells 40(3):163-168. https ://doi. org/10.14348 /molce lls.2017.0011
  11. Fang Y, Wang J, Yao L, Li C, Wang J, Liu Y, Tao X, Sun H, Liao H (2018) The adhesion and migration of microglia to beta-amyloid (Abeta) is decreased with aging and inhibited by Nogo/NgR pathway. J Neuroinflamm 15(1):210. https ://doi.org/10.1186/ s1297 4-018-1250-1
  12. Fu P, Tang R, Yu Z, Li C, Chen X, Xie M, Wang W, Luo X (2016) Rho-associated kinase inhibitors promote microglial uptake via the ERK signaling pathway. Neurosci Bull 32(1):83-91. https :// doi.org/10.1007/s1226 4-016-0013-1 · DOI
  13. Fu W, Vukojevic V, Patel A, Soudy R, MacTavish D, Westaway D, Kaur K, Goncharuk V, Jhamandas J (2017) Role of microglial amylin receptors in mediating beta amyloid (Abeta)induced inflammation. J Neuroinflamm 14(1):199. https ://doi. org/10.1186/s1297 4-017-0972-9 · DOI
  14. Holtzman DM, Morris JC, Goate AM (2011) Alzheimer's disease: the challenge of the second century. Sci Transl Med 3(77):77sr71. https ://doi.org/10.1126/scitr anslm ed.30023 69 · DOI
  15. Huang WC, Yen FC, Shie FS, Pan CM, Shiao YJ, Yang CN, Huang FL, Sung YJ, Tsay HJ (2010) TGF-beta1 blockade of microglial chemotaxis toward Abeta aggregates involves SMAD signaling and down-regulation of CCL5. J Neuroinflamm 7:28. https ://doi. org/10.1186/1742-2094-7-28 · DOI
  16. Ishizaki T, Uehata M, Tamechika I, Keel J, Nonomura K, Maekawa M, Narumiya S (2000) Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol Pharmacol 57(5):976-983
  17. Jeon YJ, Won HY, Moon MY, Choi WH, Chang CH, Lee JY, Kim J, Kim SC, Kim YS, Park JB (2008) Interaction of microglia and amyloid-beta through beta2-integrin is regulated by RhoA. Neuroreport 19(17):1661-1665. https ://doi.org/10.1097/WNR.0b013 e3283 140f1 0 · DOI
  18. Jo M, Thomas KS, Somlyo AV, Somlyo AP, Gonias SL (2002) Cooperativity between the Ras-ERK and Rho-Rho kinase pathways in urokinase-type plasminogen activator-stimulated cell migration. J Biol Chem 277(14):12479-12485. https ://doi.org/10.1074/jbc. M1111 47200 · DOI
  19. Justus CR, Leffler N, Ruiz-Echevarria M, Yang LV (2014) In vitro cell migration and invasion assays. J Vis Exp. https ://doi. org/10.3791/51046 · DOI
  20. Meraz-Rios MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernandez J, Campos-Pena V (2013) Inflammatory process in Alzheimer's disease. Front Integr Neurosci 7:59. https ://doi.org/10.3389/ fnint .2013.00059
  21. Moon MY, Kim HJ, Li Y, Kim JG, Jeon YJ, Won HY, Kim JS, Kwon HY, Choi IG, Ro E, Joe EH, Choe M, Kwon HJ, Kim HC, Kim YS, Park JB (2013) Involvement of small GTPase RhoA in the regulation of superoxide production in BV2 cells in response to fibrillar Abeta peptides. Cell Signal 25(9):1861-1869. https ://doi. org/10.1016/j.cells ig.2013.05.023 · DOI
  22. Mosher KI, Wyss-Coray T (2014) Microglial dysfunction in brain aging and Alzheimer's disease. Biochem Pharmacol 88(4):594604. https ://doi.org/10.1016/j.bcp.2014.01.008 · DOI · Paper page
  23. Mueller BK, Mack H, Teusch N (2005) Rho kinase, a promising drug target for neurological disorders. Nat Rev Drug Discov 4(5):387398. https ://doi.org/10.1038/nrd17 19 · DOI
  24. Park JC, Baik SH, Han SH, Cho HJ, Choi H, Kim HJ, Choi H, Lee W, Kim DK, Mook-Jung I (2017) Annexin A1 restores Abeta1-42 -induced blood-brain barrier disruption through the inhibition of RhoA-ROCK signaling pathway. Aging Cell 16(1):149-161. https ://doi.org/10.1111/acel.12530 · DOI
  25. Raftopoulou M, Hall A (2004) Cell migration: Rho GTPases lead the way. Dev Biol 265(1):23-32
  26. Ransohoff RM (2016) A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19(8):987-991. https ://doi.org/10.1038/ nn.4338
  27. Scheiblich H, Bicker G (2017) Regulation of microglial phagocytosis by RhoA/ROCK-inhibiting drugs. Cell Mol Neurobiol 37(3):461473. https ://doi.org/10.1007/s1057 1-016-0379-7 · DOI
  28. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9(7):671-675
  29. Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 8(6):595-608. https ://doi. org/10.15252 /emmm.20160 6210
  30. Cuadrado A, Harte M, Simons P, Srivastava DP, Killick R (2018) Amyloid beta synaptotoxicity is Wnt-PCP dependent and blocked by Fasudil. Alzheimers Dement 14(3):306-317. https ://doi. org/10.1016/j.jalz.2017.09.008 · DOI
  31. Sheng JG, Mrak RE, Griffin WS (1997) Neuritic plaque evolution in Alzheimer's disease is accompanied by transition of activated microglia from primed to enlarged to phagocytic forms. Acta Neuropathol 94(1):1-5
  32. Sindi S, Mangialasche F, Kivipelto M (2015) Advances in the prevention of Alzheimer's disease. F1000Prime Rep 7:50. https ://doi. org/10.12703 /P7-50
  33. Sit ST, Manser E (2011) Rho GTPases and their role in organizing the actin cytoskeleton. J Cell Sci 124(Pt 5):679-683. https ://doi. org/10.1242/jcs.06496 4 · DOI
  34. Small DH, Mok SS, Bornstein JC (2001) Alzheimer's disease and Abeta toxicity: from top to bottom. Nat Rev Neurosci 2(8):595598. https ://doi.org/10.1038/35086 072 · DOI
  35. Solito E, Sastre M (2012) Microglia function in Alzheimer's disease. Front Pharmacol 3:14. https ://doi.org/10.3389/fphar .2012.00014 · DOI
  36. Tsushima H, Emanuele M, Polenghi A, Esposito A, Vassalli M, Barberis A, Difato F, Chieregatti E (2015) HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity. Nat Commun 6:7781. https ://doi.org/10.1038/ncomm s8781 · DOI
  37. Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation. J Neuroinflamm 9:156. https ://doi.org/10.1186/1742-2094-9-156 · DOI
  38. Venneti S, Wiley CA, Kofler J (2009) Imaging microglial activation during neuroinflammation and Alzheimer's disease. J Neuroimmune Pharmacol 4(2):227-243. https ://doi.org/10.1007/s1148 1-008-9142-2 · DOI
  39. Wolf SA, Boddeke HW, Kettenmann H (2017) Microglia in physiology and disease. Annu Rev Physiol 79:619-643. https ://doi. org/10.1146/annur ev-physi ol-02251 6-03440 6 · DOI
  40. Xu Y, Wang D, Luo Y, Li W, Shan Y, Tan X, Zhu C (2015) Beta amyloid-induced upregulation of death receptor 6 accelerates the toxic effect of N-terminal fragment of amyloid precursor protein. Neurobiol Aging 36(1):157-168. https ://doi.org/10.1016/j.neuro biola ging.2014.07.027 · DOI

Cited by

Sorted by citations

Authors
Zhang, X., Ye, P., Wang, D., Liu, Y., Cao, L., Wang, Y., Xu, Y., & Zhu, C.
Affiliations
Shanghai Medical College of Fudan University (CN)
Corresponding author
  • Xu, Yuxia
  • Zhu, Cuiqing
ORCID
Venue
Cellular and Molecular Neurobiology
Publisher
Springer Science and Business Media LLC
Published
2019-03-09
Volume
39
Issue
5
Pages
637-650
ISSN
  • 0272-4340 (ISSN-L)
  • 1573-6830
DOI
10.1007/s10571-019-00668-6
PMC
PMC11462834
OpenAlex
W2922494315
Cited by
40
References
2
Citations by year
2026: 6 · 2025: 4 · 2024: 14 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 2
FWCI
1.30
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cellular and Molecular Neurobiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (81471285, 31671041)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
RhoA/ROCK signaling, amyloid-beta, microglia, Alzheimer's disease, microglial chemotaxis, neuroinflammation, reactive microglia, APP/PS1 mice, fasudil, Y-27632, RhoA inhibitor, microglial migration
MeSH terms
Animals, Cell Line, Chemotaxis, Inflammation, Mice, Inbred C57BL, Models, Biological, Signal Transduction, Antigens, CD, Amyloid beta-Peptides, Apoptosis, Microglia, Neuroprotective Agents, rhoA GTP-Binding Protein, rho-Associated Kinases, Protein Aggregates

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