Fibrillar Amyloid-β_1-42 Modifies Actin Organization Affecting the Cofilin Phosphorylation State: A Role for Rac1/cdc42 Effector Proteins and the Slingshot Phosphatase

Article type: Research Article

Authors: Mendoza-Naranjo, Ariadna^a | Contreras-Vallejos, Erick^b | Henriquez, Daniel R.^b | Otth, Carola^c | Bamburg, James R.^d | Maccioni, Ricardo B.^a | Gonzalez-Billault, Christian^{b; *}

Affiliations: [a] Laboratory of Cellular and Molecular Neurosciences, University of Chile and International Center for Biomedicine (ICC), Santiago, Chile | [b] Laboratory of Cellular and Neuronal Dynamics, Department of Biology Faculty of Sciences, Universidad de Chile, Las Palmeras, Nunoa, Santiago, Chile | [c] Clinical Microbiology Institute, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile | [d] Department of Biochemistry and Molecular Biology, Program in Molecular, Cellular and Integrative Neuroscience, Colorado State University, Fort Collins, CO, USA

Correspondence: [*] Correspondence to: Dr. Christian González-Billault, Laboratory of Cellular and Neuronal Dynamics, Department of Biology, Faculty of Sciences, Las Palmeras 3425, Nunoa, Santiago, Chile. Tel.: +56 2 9787442; Fax: +56 2 2712983; E-mail: [email protected].

Abstract: The neuronal cytoskeleton regulates numerous processes that occur in normal homeostasis. Under pathological conditions such as those of Alzheimer's disease (AD), major alterations in cytoskeleton organization have been observed and changes in both microtubules and actin filaments have been reported. Many neurodegenerative consequences of AD are linked to the production and accumulation of amyloid peptides (Aβ) and their oligomers, produced from the internal cleavage of the amyloid-β protein precursor. We previously reported that fibrillar Aβ1-42 (fAβ) treatment of hippocampal neurons induced an increase in Rac1 and Cdc42 activities linking fAβ effects with changes in actin dynamics. Here we show fAβ-induces increased activity of PAK1 and cyclin-dependent kinase 5, and that p21-activated kinase (PAK1) activation targets the LIMK1-cofilin signaling pathway. Increased cofilin dephosphorylation under conditions of enhanced LIM-Kinase 1 (LIMK1) activity suggests that fAβ co-stimulates bifurcating pathways impacting cofilin phosphorylation. Overexpression of slingshot (SSH) prevents the augment of F-actin induced by fAβ after 24 h, suggesting that fAβ-induced changes in actin assembly involve both LIMK1 and SSH. These results suggest that fAb may alter the PAK1/LIMK1/cofilin axis and therefore actin organization in AD.

Keywords: Actin dynamics, cofilin, cultured hippocampal neurons, cytoskeleton, LIMK1, neurodegeneration, SSH

DOI: 10.3233/JAD-2012-101575

Journal: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 63-77, 2012