title: Involvement of the γ-secretase-mediated EphA4 signaling pathway in synaptic pathogenesis of Alzheimer's disease.
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.
authors.affiliation: KAN Research Institute, Kobe, Japan.
authors.forename: Chiyuki
authors.initials: C
authors.lastname: Matsui
authors.forename: Eiji
authors.initials: E
authors.lastname: Inoue
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.forename: Kohei
authors.initials: K
authors.lastname: Arita
authors.forename: Maki
authors.initials: M
authors.lastname: Deguchi-Tawarada
authors.forename: Aki
authors.initials: A
authors.lastname: Togawa
authors.forename: Akio
authors.initials: A
authors.lastname: Yamada
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Takai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051381:Rats; D036122:Receptor, EphA4 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000378:metabolism / Q000473:pathology
chemical_list: D036122:Receptor, EphA4; D053829:Amyloid Precursor Protein Secretases