Secretase-Independent and RhoGTPase/PAK/ERK-Dependent Regulation of Cytoskeleton Dynamics in Astrocytes by NSAIDs and Derivatives

Article type: Research Article

Authors: Lichtenstein, Mathieu P.^{a; b; 1} | Carriba, Paulina^{a; b; 1} | Baltrons, María Antonia^{b; c} | Wojciak-Stothard, Beata^d | Peterson, Jeffrey R.^e | García, Agustina^{b; c; 1} | Galea, Elena^{a; b; f; 1; *}

Affiliations: [a] Institut de Neurociènces, Universitat Autònoma de Barcelona, Spain | [b] Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Spain | [c] Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Spain | [d] Department of Experimental Medicine and Toxicology, Hammersmith Campus, Imperial College London, UK | [e] Fox Chase Cancer Center, Philadelphia, PA, USA | [f] Institut Català d'Estudis Avançats (ICREA), Spain

Correspondence: [*] Correspondence to: Elena Galea, PhD, Institut of Neurociències, Edifici M Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain. Tel.: +34 93 586 8143; Fax: +34 93 581 1575; E-mail: galea.inc@gmail.com.

Note: [1] Equal author contribution.

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.

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

DOI: 10.3233/JAD-2010-101332

Journal: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1135-1155, 2010