Phosphorylation of ADF/Cofilin by LIM-kinase mediates amyloid ƒÒ-induced Degeneration: A potential mechanism of neuronal dystrophy in Alzheimer disease.

HEREDIA, L.; HELGUERA, P.; DEOLMOS, S.; KEDIKIAN, G.; SOLA VIGO, F.; LAFERLA, F.; STAUFENBIEL, M.; DEOLMOS, J.; BUSCIGLIO, J.; CACERES, A.; LORENZO, A.

JOURNAL OF NEUROSCIENCE

American Society of Neuroscience

Año: 2006 vol. 26 p. 6533 - 6542

0270-6474

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. Asynthetic 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.