LIM-kinase mediates Amyloid beta-induced neuronal dystrophy in Alzheimer´s disease.

HEREDIA L; DE OLMOS S; KEDIKIAN G; SOLA VIGO F; LORENZO A

Santiago-Chile

Simposio; First Chilean International Symposium on Neurodegenerative diseases; 2005

Centro de Regulación Celular y Patología - Pontificia Universidad Católica de Chile

Amyloid plaques, mainly composed of Amyloid beta fibrils (fAbeta), and surrounded by dystrophic neurites are characteristic pathological features of Alzheimer´s disease (AD).  Deposition of fAbeta plays a critical role in AD pathology, and in the development of neuronal dystrophy.  Deposition of fAbeta triggers aberrant activation of focal adhesion proteins, and the formation of abnormal focal adhesion structures suggesting the activation of a mechanism of maladaptative plasticity.  Focal adhesions are actin-based structures that provide a structural link between the extracellular matrix and the cytoskeleton.  To gain further insight in the molecular mechanism of neuronal degeneration in AD, here we explored the involvement of LIM kinase 1 (LIMK1), actin-depolymerizing factor and cofilin (ADF/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 significantly increase the levels of the inactive, Ser3-phosphorylated ADF/Cofilin, and also that of the active, Thr508-phosphorylated LIMK1 (P-LIMK1).  These events are accompanied by a dramatic remodeling of actin filaments and neuritic dystrophy.  Treatment of hippocampal cultures with S3 peptide, a synthetic peptide that acts as a specific competitor for ADF/Cofilin phosphorylation by P-LIMK1, inhibited fAbeta-induced ADF/Cofilin phosphorylation, preventing actin filaments remodeling, and significantly reducing neuritic dystrophy.  These observations suggest that actin remodeling, mediated by altered activities of LIMK1 and ADF/Cofilin, is required for Ab-induced neuronal dystrophy in vitro.  To address the potential involvement of LIMK1 in AD we performed immunofluorescence analysis of human cortical brain tissue of control and AD subjects.  In control tissue low levels of P-LIMK1-positive neurons was observed, and similar low levels of P-LIMK1 was found in AD brain tissue in areas devoid of Abeta pathology.  On the contrary, in areas with Abeta deposition significantly higher levels of P-LIMK1 were found.  High levels of P-LIMK1 were observed in neurons depicting signs of AD-pathology, such as intracellular Abeta and pre-tangle phosphorylated tau, suggesting that increased LIMK1 activity associated with amyloid plaques may participate in neuronal degeneration.  Thus, abnormal LIMK1 activation may play a role in neuronal dystrophy in AD brain.