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.
Subject(s)
Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Brain/metabolism , Receptor, EphA4/metabolism , Signal Transduction/physiology , Aged , Aged, 80 and over , Alzheimer Disease/pathology , Animals , Blotting, Western , Brain/pathology , Humans , Rats , Synapses/metabolism , Synapses/pathologyABSTRACT
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.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Dendrites/enzymology , Receptor, EphA4/metabolism , Receptor, EphA4/physiology , Synapses/physiology , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Animals , Dimethyl Sulfoxide/pharmacology , Hippocampus/enzymology , Humans , Mice , Neurofibrillary Tangles/pathology , Neurons/physiology , Rats , Spine/cytology , Spine/drug effects , Spine/pathologyABSTRACT
The rice species Oryza sativa is considered to be a model plant because of its small genome size, extensive genetic map, relative ease of transformation and synteny with other cereal crops. Here we report the essentially complete sequence of chromosome 1, the longest chromosome in the rice genome. We summarize characteristics of the chromosome structure and the biological insight gained from the sequence. The analysis of 43.3 megabases (Mb) of non-overlapping sequence reveals 6,756 protein coding genes, of which 3,161 show homology to proteins of Arabidopsis thaliana, another model plant. About 30% (2,073) of the genes have been functionally categorized. Rice chromosome 1 is (G + C)-rich, especially in its coding regions, and is characterized by several gene families that are dispersed or arranged in tandem repeats. Comparison with a draft sequence indicates the importance of a high-quality finished sequence.
