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The Journal of Neuroscience, January 15, 2003, 23(2):493-502
Aberrant Activation of Focal Adhesion Proteins Mediates Fibrillar
Amyloid  -Induced Neuronal Dystrophy
Elizabeth A.
Grace and
Jorge
Busciglio
Department of Neuroscience, University of Connecticut Health
Center, Farmington, Connecticut 06030
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  (A) peptides induces progressive neuritic
dystrophy accompanied by a marked loss of synaptophysin immunoreactivity (Grace et al., 2002). Here, we report that fibrillar A-induced neuronal dystrophy is mediated by the activation of focal
adhesion (FA) proteins and the formation of aberrant FA structures
adjacent to A 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 A 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
A-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 A may induce neuronal dystrophy by
triggering a maladaptive plastic response mediated by FA protein activation and tau hyperphosphorylation.
Key words:
Alzheimer's disease; amyloid ; senile plaques; neuronal dystrophy; neurodegeneration; focal adhesion
Copyright © 2003 Society for Neuroscience 0270-6474/03/232493-10$05.00/0
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