EphA4 is a receptor tyrosine kinase that regulates neuron–glial communication in the adult hippocampus and is important for synaptic plasticity. Emerging studies have validated the theory that dysregulated EphA4 signaling is involved in abnormal hippocampal synaptic function and impaired cognition in Alzheimer’s disease (AD) progression. Nonetheless, the underlying mechanisms remain unclear. Here, we showed that while EphA4 mRNA is highly expressed in the hippocampus of adult mice, its gene expression aberrantly increased in both hippocampal neurons and astrocytes. This suggests the role of EphA4 in AD pathogenesis. Thus, to examine the role of EphA4 in AD progression, we inhibited EphA4 kinase activity in 12-month-old APP/PS1 mice by using KYL, a peptide inhibitor. Accordingly,...[ Read more ]

EphA4 is a receptor tyrosine kinase that regulates neuron–glial communication in the adult hippocampus and is important for synaptic plasticity. Emerging studies have validated the theory that dysregulated EphA4 signaling is involved in abnormal hippocampal synaptic function and impaired cognition in Alzheimer’s disease (AD) progression. Nonetheless, the underlying mechanisms remain unclear. Here, we showed that while EphA4 mRNA is highly expressed in the hippocampus of adult mice, its gene expression aberrantly increased in both hippocampal neurons and astrocytes. This suggests the role of EphA4 in AD pathogenesis. Thus, to examine the role of EphA4 in AD progression, we inhibited EphA4 kinase activity in 12-month-old APP/PS1 mice by using KYL, a peptide inhibitor. Accordingly, EphA4 blockade by KYL ameliorated Aβ level, a hallmark of AD. It also rescued the loss of excitatory synapses in the postsynaptic CA1 region in the hippocampus in APP/PS1 mice. Furthermore, KYL treatment reversed the hyperactivation of hippocampal astrocytes in APP/PS1 mice, as indicated by the reversal of abnormal astrocyte morphology and decreased expression of GFAP, an activated astrocyte marker. Specifically, APP/PS1 mice had an enlarged subpopulation of neurotoxic A1 astrocytes that expressed complement C3, a cell marker; EphA4 blockade reduced this astrocytic subpopulation. Thus, our findings collectively demonstrate that EphA4 signaling mediates excitatory synaptic loss and astrocyte reactivity in the hippocampus during AD progression. Therefore, we will continue to investigate the mechanism by which EphA4 regulates astrocyte reactivity and the loss of hippocampal excitatory synapses in AD pathogenesis.