Skip to main content
SpringerLink
Log in

Nonsteroidal anti-inflammatory drugs attenuate amyloid-β protein-induced actin cytoskeletal reorganization through Rho signaling modulation

Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Amyloid-β protein (Aβ) neurotoxicity occurs along with the reorganization of the actin-cytoskeleton through the activation of the Rho GTPase pathway. In addition to the classical mode of action of the non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin, and ibuprofen have Rho-inhibiting effects. In order to evaluate the role of the Rho GTPase pathway on Aβ-induced neuronal death and on neuronal morphological modifications in the actin cytoskeleton, we explored the role of NSAIDS in human-differentiated neuroblastoma cells exposed to Aβ. We found that Aβ induced neurite retraction and promoted the formation of different actin-dependent structures such as stress fibers, filopodia, lamellipodia, and ruffles. In the presence of Aβ, both NSAIDs prevented neurite collapse and formation of stress fibers without affecting the formation of filopodia and lamellipodia. Similar results were obtained when the downstream effector, Rho kinase inhibitor Y27632, was applied in the presence of Aβ. These results demonstrate the potential benefits of the Rho-inhibiting NSAIDs in reducing Aβ-induced effects on neuronal structural alterations.

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

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

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

References

  • Bamburg JR, Bernstein BW (2016) Actin dynamics and cofilin-actin rods in alzheimer disease. Cytoskeleton (Hoboken) 73:477–497

    Article  CAS  Google Scholar 

  • Bishop AL, Hall A (2000) Rho GTPases and their effector proteins. Biochem J 348:241–255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borm B, Requardt RP, Herzog V, Kirfel G (2005) Membrane ruffles in cell migration: indicators of inefficient lamellipodia adhesion and compartments of actin filament reorganization. Exp Cell Res 302:83–95

    Article  CAS  PubMed  Google Scholar 

  • Da Silva JS, Medina M, Zuliani C, Di Nardo A, Witke W, Dotti CG (2003) RhoA/ROCK regulation of neuritogenesis via profilin IIa-mediated control of actin stability. J Cell Biol 162:1267–1279

    Article  PubMed  PubMed Central  Google Scholar 

  • Davis RC, Maloney MT, Minamide LS, Flynn KC, Stonebraker MA, Bamburg JR (2009) Mapping cofilin-actin rods in stressed hippocampal slices and the role of cdc42 in amyloid-beta-induced rods. J Alzheimers Dis 18:35–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dill J, Patel AR, Yang XL, Bachoo R, Powell CM, Li SA (2010) Molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. J Neurosci 30:963–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE (2003) NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 112:440–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferrera P, Arias C (2005) Differential effects of COX inhibitors against beta-amyloid-induced neurotoxicity in human neuroblastoma cells. Neurochem Int 47:589–596

    Article  CAS  PubMed  Google Scholar 

  • Fu Q, Hue J, Li S (2007) Nonsteroidal anti-inflammatory drugs promote axon regeneration via RhoA inhibition. J Neurosci 27:4154–4164

    Article  CAS  PubMed  Google Scholar 

  • Ghosh M, Song X, Mouneimne G, Sidani M, Lawrence DS, Condeelis JS (2004) Cofilin promotes actin polymerization and defines the direction of cell motility. Science 304:743–746

    Article  CAS  PubMed  Google Scholar 

  • Govek EE, Newey SE, Van Aelst L (2005) The role of the Rho GTPases in neuronal development. Genes Dev 19:191–249

    Article  Google Scholar 

  • Hall A, Nobes CD (2000) Rho GTPases: molecular switches that control the organization and dynamics of the actin cytoskeleton. Philos Trans R Soc Lond B Biol Sci 355:965–970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hashimoto M, Masliah E (2003) Cycles of aberrant synaptic sprouting and neurodegeneration in Alzheimer’s and dementia with Lewy bodies. Neurochem Res 28:1743–1756

    Article  CAS  PubMed  Google Scholar 

  • Henderson BW, Gentry EG, Rush T, Troncoso JC, Thambisetty M, Montine TJ, Herskowitz JH (2016) Rho-associated protein kinase 1 (ROCK1) is increased in Alzheimer’s disease and ROCK1 depletion reduces amyloid-β levels in brain. J Neurochem 138:525–531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herskowitz JH, Feng Y, Mattheyses AL, Hales CM, Higginbotham LA, Duong DM, Montine TJ, Troncoso JC, Thambisetty M, Seyfried NT, Levey AI, Lah JJ (2013) Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer’s disease mouse model. J Neurosci 33:19086–19098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huesa G, Baltrons MA, Gómez-Ramos P, Morán A, García A, Hidalgo J, Francés S, Santpere G, Ferrer I, Galea E (2010) Altered distribution of RhoA in Alzheimer’s disease and AβPP overexpressing mice. J Alzheimers Dis 19:37–56

    Article  PubMed  Google Scholar 

  • Kopp MA, Liebscher T, Niedeggen A, Laufer S, Brommer B, Jungehulsing GJ, Strittmatter SM, Dirnagl U, Schwab JM (2012) Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury. Cell Tissue Res 349:119–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo L (2002) Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. Annu Rev Cell Dev Biol 18:601–635

    Article  CAS  PubMed  Google Scholar 

  • Maloney MT, Minamide LS, Kinley AW, Boyle JA, Bamburg JR (2005) Beta-secretase-cleaved amyloid precursor protein accumulates at actin inclusions induced in neurons by stress or amyloid beta: a feedforward mechanism for Alzheimer’s disease. J Neurosci 25:11313–11321

    Article  CAS  PubMed  Google Scholar 

  • Masliah E, Miller A, Terry RD (1993) The synaptic organization of the neocortex in Alzheimer’s disease. Med Hypotheses 41:334–340

    Article  CAS  PubMed  Google Scholar 

  • Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW Jr, Morris JC (2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56:127–129

    Article  CAS  PubMed  Google Scholar 

  • Mendoza-Naranjo A, Gonzalez-Billault C, Maccioni RB (2007) Abeta1-42 stimulates actin polymerization in hippocampal neurons through Rac1 and Cdc42 Rho GTPases. J Cell Sci 120:279–288

    Article  CAS  PubMed  Google Scholar 

  • Mendoza-Naranjo A, Contreras-Vallejos E, Henriquez DR, Otth C, Bamburg JR, Maccioni RB, Gonzalez-Billault C (2012) Fibrillar amyloid-β1-42 modifies actin organization affecting the cofilin phosphorylation state: a role for Rac1/cdc42 effector proteins and the slingshot phosphatase. J Alzheimers Dis 29:63–77

  • Minamide LS, Striegl AM, Boyle JA, Meberg PJ, Bamburg JR (2000) Neurodegenerative stimuli induce persistent ADF/cofilin-actin rods that disrupt distal neurite function. Nat Cell Biol 2:628–636

    Article  CAS  PubMed  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

  • Petratos S, Li QX, George AJ, Hou X, Kerr ML, Unabia SE, Hatzinisiriou I, Maksel D, Aguilar MI, Small DH (2008) The beta-amyloid protein of Alzheimer’s disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism. Brain 131:90–108

    Article  PubMed  Google Scholar 

  • Pollard TD, Borisy GG (2003) Cellular motility driven by assembly and disassembly of actin filaments. Cell 112:453–465

    Article  CAS  PubMed  Google Scholar 

  • Roloff F, Scheiblich H, Dewitz C, Dempewolf S, Stern M, Bicker G (2015) Enhanced neurite outgrowth of human model (NT2) neurons by small-molecule inhibitors of Rho/ROCK signaling. PLoS ONE. doi:10.1371/journal.pone.0118536

    PubMed  PubMed Central  Google Scholar 

  • Sfakianos MK, Eisman A, Gourley SL, Bradley WD, Scheetz AJ, Settleman J, Taylor JR, Greer CA, Williamson A, Koleske AJ (2007) Inhibition of Rho via Arg and p190RhoGAP in the postnatal mouse hippocampus regulates dendritic spine maturation, synapse and dendrite stability, and behavior. J Neurosci 27:10982–10992

    Article  CAS  PubMed  Google Scholar 

  • Spence EF, Soderling SH (2015) Actin out: regulation of the synaptic cytoskeleton. J Biol Chem 290:28613–28622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Svitkina T, Lin WH, Webb DJ, Yasuda R, Wayman GA, Van Aelst L, Soderling SH (2010) Regulation of the postsynaptic cytoskeleton: roles in development, plasticity, and disorders. J Neurosci 30:14937–14942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swanger SA, Mattheyses AL, Gentry EG, Herskowitz JH (2016) ROCK1 and ROCK2 inhibition alters dendritic spine morphology in hippocampal neurons. Cell Logist. 5(4):e1133266

    Article  PubMed  PubMed Central  Google Scholar 

  • Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30(4):572–580

    Article  CAS  PubMed  Google Scholar 

  • 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. doi:10.1038/ncomms8781

    PubMed  Google Scholar 

  • Wang X, Budel S, Baughman K, Gould G, Song KH, Strittmatter SM (2009) Ibuprofen enhances recovery from spinal cord injury by limiting tissue loss and stimulating axonal growth. J Neurotrauma 26:81–95

    Article  PubMed  PubMed Central  Google Scholar 

  • Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Ozols V, Fauq VA, Golde TE, Koo EH (2003) Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid β 42 production by direct modulation of gamma-secretase activity. Biol Chem 278:31831–31837

    Article  CAS  Google Scholar 

  • Xing B, Li H, Wang H, Mukhopadhyay D, Fisher D, Gilpin CJ, Li S (2011) RhoA-inhibiting NSAIDs promote axonal myelination after spinal cord injury. Exp Neurol 231:247–260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, Gonzalez-DeWhitt PA, Gelfanova V, Hale JE, May PC, Paul SM, Ni B (2003) Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science 302:1215-1217

  • Zhu X, Raina AK, Boux H, Simmons ZL, Takeda A, Smith MA (2000) Activation of oncogenic pathways in degenerating neurons in Alzheimer disease. Int J Dev Neurosci 18:433–437

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants to CA (PAPIIT IN202615) and to AZ (PAPIIT IN203015).

Author contributions

C. Arias contributed to conception and design and wrote the manuscript. P. Ferrera and A. Zepeda performed experiments and data analysis.

Author information

Authors and Affiliations

  1. Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, AP 70-228, 04510, México, DF, Mexico

    Patricia Ferrera, Angélica Zepeda & Clorinda Arias

Authors
  1. Patricia Ferrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angélica Zepeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clorinda Arias
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clorinda Arias.

Ethics declarations

Conflict of interest

The authors declare that th have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ferrera, P., Zepeda, A. & Arias, C. Nonsteroidal anti-inflammatory drugs attenuate amyloid-β protein-induced actin cytoskeletal reorganization through Rho signaling modulation. Cell Mol Neurobiol 37, 1311–1318 (2017). https://doi.org/10.1007/s10571-017-0467-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-017-0467-3

Keywords

search

Navigation