Secretase-independent and RhoGTPase/PAK/ERK-dependent regulation of cytoskeleton dynamics in astrocytes by NSAIDs and derivatives

Mathieu P. Lichtenstein, Paulina Carriba, María Antonia Baltrons, Beata Wojciak-Stothard, Jeffrey R. Peterson, Agustina García, Elena Galea

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

Abstract

Profens like ibuprofen, R-flurbiprofen, or CHF5074 are being considered for the treatment of Alzheimer's disease because epidemiological data indicates that non-steroidal anti-inflammatory drugs are protective against neurodegeneration. Rho-GTPases are small G proteins, including RhoA, Cdc42, and Rac1, which control cytoskeleton dynamics. Because ibuprofen promotes axon growth via RhoA in neurons, we examined whether profens modulate astrocyte plasticity via Rho-GTPases. We report that ibuprofen (100-500 μM), R-flurbiprofen (100-500 μM), and CHF5074 (10-30 μM) caused a concentration-dependent stellation of astrocytes in primary cultures, associated with the reorganization of GFAP and actin filaments. The stellation was independent of COX2, α-, β- or γ-secretase as judged by the lack of effect of inhibitors of these enzymes. RhoA, PAK, and Cdc42, but not Rac1, accounted for the profen-mediated stellation, as concluded from the joint analyses of activities and reversal experiments with adenoviral or pharmacological manipulations. Ibuprofen accelerated migration in a scratch-wound assay, while R-flurbiprofen had no effect and CHF5074 caused deceleration. Cell polarity regulation by Cdc42 and ERK1/2 may underlie the paradoxical effects of profens on migration. We conclude that profens regulate cytoskeleton dynamics in astrocytes via Rho-GTPases, PAK, and ERK1/2. Since migration is a hallmark of astrocyte response during inflammation we propose that, in addition to (or instead of) lowering amyloid-β42 via secretases, ibuprofen and its derivatives may prevent Alzheimer's disease instead of AD by modulating astrocyte reactivity through Rho-GTPase/PAK/ERK-dependent signaling. © 2010 - IOS Press and the authors. All rights reserved.
Original languageEnglish
Pages (from-to)1135-1155
JournalJournal of Alzheimer's Disease
Volume22
DOIs
Publication statusPublished - 1 Jan 2010

Keywords

  • Actin
  • Alzheimer's disease
  • CHF5074
  • Cdc42
  • IPA3
  • NSAIDs
  • R-Flurbiprofen
  • Rac1
  • RhoA
  • astrocytes
  • ibuprofen

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