Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid beta-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer's disease.
Deposition of fibrillar amyloid beta (fAbeta) plays a critical role in Alzheimer's disease (AD). We have shown recently that fAbeta-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 Abeta-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 fAbeta 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 fAbeta-induced ADF/cofilin phosphorylation, preventing actin filament remodeling and neuronal degeneration, indicating the involvement of LIMK1 in Abeta-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 Abeta and pretangle phosphorylated tau. Thus, LIMK1 activation may play a key role in AD pathology.
Heredia
Lorena
L
Laboratory of Experimental Neuropathology, Instituto de Investigación Médica Mercedes y Martín Ferreyra/Consejo Nacional de Investigaciones Científicas y Técnicas, 5000 Córdoba, Argentina.
Helguera
Pablo
P
de Olmos
Soledad
S
Kedikian
Gabriela
G
Solá Vigo
Francisco
F
LaFerla
Frank
F
Staufenbiel
Matthias
M
de Olmos
José
J
Busciglio
Jorge
J
Cáceres
Alfredo
A
Lorenzo
Alfredo
A
D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000544:Alzheimer Disease / Q000150:complications / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D054461:Lim Kinases; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D013997:Time Factors
D051339:Actin Depolymerizing Factors; D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515894:Limk1 protein, rat