Alzheimer’s disease (AD), characterized by memory decline and cognition impairment, is one of the most common neurodegenerative diseases. There is currently no way to prevent or cure AD, in part because its underlying pathogenesis is not fully understood. Our laboratory previously demonstrated that blockade of EphA4 signaling reverses the synaptic deficits in APP/PS1 mice, an AD transgenic mouse model, although the underlying mechanism is unclear. Given that EphA4 mediates the regulation of GLT1, the predominant glutamate transporter in the hippocampus, through the EphA4/ephrinA3 reverse signaling pathway, EphA4 may mediate the pathology of AD through the regulation of GLT1. The present study showed that synaptic fatigue, an activity-dependent form of short-term synaptic plasticity that...[ Read more ]

Alzheimer’s disease (AD), characterized by memory decline and cognition impairment, is one of the most common neurodegenerative diseases. There is currently no way to prevent or cure AD, in part because its underlying pathogenesis is not fully understood. Our laboratory previously demonstrated that blockade of EphA4 signaling reverses the synaptic deficits in APP/PS1 mice, an AD transgenic mouse model, although the underlying mechanism is unclear. Given that EphA4 mediates the regulation of GLT1, the predominant glutamate transporter in the hippocampus, through the EphA4/ephrinA3 reverse signaling pathway, EphA4 may mediate the pathology of AD through the regulation of GLT1. The present study showed that synaptic fatigue, an activity-dependent form of short-term synaptic plasticity that is important for learning and memory, is enhanced in APP/PS1 mice. Blockade of EphA4 signaling by KYL peptide abolished the enhanced synaptic fatigue in APP/PS1 mice. In addition, the enhancement of synaptic fatigue in APP/PS1 mice was mediated by GLT1, implying that EphA4 signaling modulates the dysfunction of GLT1 in APP/PS1 mice. Furthermore, dysregulation of GLT1 increased extracellular glutamate concentration and led to subsequent deficits of synaptic plasticity as demonstrated by impaired single-burst long-term potentiation. These findings collectively suggest that both EphA4 and GLT1 play important roles in the pathology of AD and may therefore be potential targets for the treatment of AD.