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The Journal of Neuroscience, June 14, 2006, 26(24):6533-6542; doi:10.1523/JNEUROSCI.5567-05.2006

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Neurobiology of Disease
Phosphorylation of Actin-Depolymerizing Factor/Cofilin by LIM-Kinase Mediates Amyloid -Induced Degeneration: A Potential Mechanism of Neuronal Dystrophy in Alzheimer's Disease

Lorena Heredia,¹ Pablo Helguera,⁴ Soledad de Olmos,² Gabriela Kedikian,¹ Francisco Solá Vigo,¹ Frank LaFerla,⁴ Matthias Staufenbiel,⁵ José de Olmos,² Jorge Busciglio,⁴ Alfredo Cáceres,³ and Alfredo Lorenzo¹

Laboratories of ¹Experimental Neuropathology, ²Neuroanatomy, and ³ Cell Biology, Instituto de Investigación Médica "Mercedes y Martín Ferreyra"/Consejo Nacional de Investigaciones Científicas y Técnicas, 5000 Córdoba, Argentina, ⁴Department of Neurobiology and Behavior, University of California, Irvine, California 92697-4550, and ⁵Novartis Institute for BioMedical Research Basel, Inc., CH-4002 Basel, Switzerland

Correspondence should be addressed to Dr. Alfredo Lorenzo, Laboratory of Experimental Neuropathology, Instituto de Investigación Médica "Mercedes y Martín Ferreyra"/Consejo Nacional de Investigaciones Científicas y Técnicas, Casilla de Correo 389, 5000 Córdoba, Argentina. Email: alorenzo{at}immf.uncor.edu

Deposition of fibrillar amyloid (fA) plays a critical role in Alzheimer's disease (AD). We have shown recently that fA-induced dystrophy requires the activation of focal adhesion proteins and the formation of aberrant focal adhesion structures, suggesting the activation of a mechanism of maladaptative plasticity in AD. Focal adhesions are actin-based structures that provide a structural link between the extracellular matrix and the cytoskeleton. To gain additional insight in the molecular mechanism of neuronal degeneration in AD, here we explored the involvement of LIM kinase 1 (LIMK1), actin-depolymerizing factor (ADF), and cofilin in A-induced dystrophy. ADF/cofilin are actin-binding proteins that play a central role in actin filament dynamics, and LIMK1 is the kinase that phosphorylates and thereby inhibits ADF/cofilin. Our data indicate that treatment of hippocampal neurons with fA increases the level of Ser3-phosphorylated ADF/cofilin and Thr508-phosphorylated LIMK1 (P-LIMK1), accompanied by a dramatic remodeling of actin filaments, neuritic dystrophy, and neuronal cell death. A synthetic peptide, S3 peptide, which acts as a specific competitor for ADF/cofilin phosphorylation by LIMK1, inhibited fA-induced ADF/cofilin phosphorylation, preventing actin filament remodeling and neuronal degeneration, indicating the involvement of LIMK1 in A-induced neuronal degeneration in vitro. Immunofluorescence analysis of AD brain showed a significant increase in the number of P-LIMK1-positive neurons in areas affected with AD pathology. P-LIMK1-positive neurons also showed early signs of AD pathology, such as intracellular A and pretangle phosphorylated tau. Thus, LIMK1 activation may play a key role in AD pathology.

Key words: amyloid ; A; LIMK1; ADF/cofilin; Alzheimer's disease; dystrophic neuritis; neuronal neurodegeneration

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Received July 21, 2005; revised April 28, 2006; accepted April 30, 2006.

Correspondence should be addressed to Dr. Alfredo Lorenzo, Laboratory of Experimental Neuropathology, Instituto de Investigación Médica "Mercedes y Martín Ferreyra"/Consejo Nacional de Investigaciones Científicas y Técnicas, Casilla de Correo 389, 5000 Córdoba, Argentina. Email: alorenzo{at}immf.uncor.edu

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