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Publications (2)15.56 Total impact

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    ABSTRACT: Loss of synapses is associated with cognitive impairment in Alzheimer's disease (AD). However, the molecular mechanism underlying this synaptic impairment is not well understood. EphA4 is a substrate of γ-secretase, and the γ-secretase-cleaved EphA4 intracellular domain (EICD) is known to enhance the formation of dendritic spines via activation of the Rac signaling pathway. Here, we show that the amount of Rac1 is significantly reduced, and correlated with the level of EICD in the frontal lobes of AD patients. Biochemical analyses revealed that the amount of membrane-associated EICD was decreased and strongly correlated with the level of membrane-associated Rac1, which is considered to be active Rac1. The synaptic scaffolding protein, postsynaptic density (PSD)-95, was specifically decreased in AD, and the amount of PSD-95 correlated with the level of Rac1. Moreover, the amounts of Rac1 and PSD-95 were negatively correlated with the extent of tau phosphorylation, which is crucial for neurofibrillary tangle formation. These results suggest that attenuation of the EICD-mediated Rac signaling pathway is involved in the synaptic pathogenesis of AD.
    Brain Pathology 03/2012; 22(6):776-87. · 4.74 Impact Factor
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    ABSTRACT: Alzheimer's disease is an age-dependent neurodegenerative disorder that is characterized by a progressive decline in cognitive function. gamma-secretase dysfunction is evident in many cases of early onset familial Alzheimer's disease. However, the mechanism by which gamma-secretase dysfunction results in memory loss and neurodegeneration is not fully understood. Here, we demonstrate that gamma-secretase is localized at synapses and regulates spine formation. We identify EphA4, one of the Ephrin receptor family members, as a substrate of gamma-secretase, and find that EphA4 processing is enhanced by synaptic activity. Moreover, overexpression of EphA4 intracellular domain increases the number of dendritic spines by activating the Rac signaling pathway. These findings reveal a function for EphA4-mediated intracellular signaling in the morphogenesis of dendritic spines and suggest that the processing of EphA4 by gamma-secretase affects the pathogenesis of Alzheimer's disease.
    The Journal of Cell Biology 06/2009; 185(3):551-64. · 10.82 Impact Factor