Actin filaments are essential components of the adhesive complex, and its dynamic reorganization provides the initial force to adapt neuronal morphology to its surrounding. ![]() We have shown recently that such early events may include the clustering of AβPP and integrin receptors at the cell surface around Aβ fibrils, the activation of focal adhesion proteins, and the formation of aberrant focal adhesion structures ( Grace and Busciglio, 2003 Heredia et al., 2004), suggesting that Aβ deposition triggers a pathological mechanism of plasticity leading to neuronal dystrophy.įocal adhesions provide a structural link between the extracellular matrix and the actin cytoskeleton. Much effort was devoted to understand the mechanism that links Aβ deposition to tau pathology as an attempt to define the events that lead to neurofibrillary tangle formation in AD ( Busciglio et al., 1995 Lee et al., 2000 Götz et al., 2001 Oddo et al., 2003), whereas less attention was put on upstream events that may trigger the dystrophic process. Aβ neurotoxicity induces neuronal dystrophy characterized by aberrant neuritic morphology, sprouting, and breakdown ( Busciglio et al., 1992 Grace et al., 2002). ![]() Aβ aggregation is required for senile plaque formation and renders Aβ neurotoxic ( Pike et al., 1991 Lorenzo and Yankner, 1994 Lambert et al., 1998). Amyloid β (Aβ), a 40–43 amino acid derivative of the metabolism of amyloid β precursor protein (AβPP), is the main constituent of senile plaques ( Hardy and Selkoe, 2002). Dystrophic neurites typically associate with senile plaques, the hallmark lesions of Alzheimer's disease (AD). Thus, LIMK1 activation may play a key role in AD pathology.ĭystrophic neurites are markedly distorted axons and dendrites that characterize Alzheimer's pathology ( Benzing et al., 1993), playing an important role in cognitive impairment in the disease ( McKee et al., 1991 Spires and Hyman, 2004). P-LIMK1-positive neurons also showed early signs of AD pathology, such as intracellular Aβ and pretangle phosphorylated tau. Immunofluorescence analysis of AD brain showed a significant increase in the number of P-LIMK1-positive neurons in areas affected with AD pathology. A synthetic peptide, S3 peptide, which acts as a specific competitor for ADF/cofilin phosphorylation by LIMK1, inhibited fAβ-induced ADF/cofilin phosphorylation, preventing actin filament remodeling and neuronal degeneration, indicating the involvement of LIMK1 in Aβ-induced neuronal degeneration in vitro. Our data indicate that treatment of hippocampal neurons with fAβ 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. ![]() 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. ![]() 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 Aβ-induced dystrophy. Focal adhesions are actin-based structures that provide a structural link between the extracellular matrix and the cytoskeleton. We have shown recently that fAβ-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. Deposition of fibrillar amyloid β (fAβ) plays a critical role in Alzheimer's disease (AD).
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