TY - JOUR T1 - Aberrant Activation of Focal Adhesion Proteins Mediates Fibrillar Amyloid β-Induced Neuronal Dystrophy JF - The Journal of Neuroscience JO - J. Neurosci. SP - 493 LP - 502 DO - 10.1523/JNEUROSCI.23-02-00493.2003 VL - 23 IS - 2 AU - Elizabeth A. Grace AU - Jorge Busciglio Y1 - 2003/01/15 UR - http://www.jneurosci.org/content/23/2/493.abstract N2 - Neuronal dystrophy is a pathological hallmark of Alzheimer's disease (AD) that is not observed in other neurodegenerative disorders that lack amyloid deposition. Treatment of cortical neurons with fibrillar amyloid β (Aβ) peptides induces progressive neuritic dystrophy accompanied by a marked loss of synaptophysin immunoreactivity (Grace et al., 2002). Here, we report that fibrillar Aβ-induced neuronal dystrophy is mediated by the activation of focal adhesion (FA) proteins and the formation of aberrant FA structures adjacent to Aβ deposits. In the AD brain, activated FA proteins are observed associated with the majority of senile plaques. Clustered integrin receptors and activated paxillin (phosphorylated at Tyr-31) and focal adhesion kinase (phosphorylated at Tyr-297) are mainly detected in dystrophic neurites surrounding Aβ plaque cores, where they colocalize with hyperphosphorylated tau. Deletion experiments demonstrated that the presence of the LIM domains in the paxillin C terminus and the recruitment of the protein-Tyr phosphatase (PTP)-PEST to the FA complex are required for Aβ-induced neuronal dystrophy. Therefore, both paxillin and PTP-PEST appear to be critical elements in the generation of the dystrophic response. Paxillin is a scaffolding protein to which other FA proteins bind, leading to the formation of the FA contact and initiation of signaling cascades. PTP-PEST plays a key role in the dynamic regulation of focal adhesion contacts in response to extracellular cues. Thus, in the AD brain, fibrillar Aβ may induce neuronal dystrophy by triggering a maladaptive plastic response mediated by FA protein activation and tau hyperphosphorylation. ER -