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Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

2014; National Academy of Sciences; Volume: 111; Issue: 27 Linguagem: Inglês

10.1073/pnas.1405803111

1091-6490

Amy K.Y. Fu, Kwok-Wang Hung, Huiqian Huang, Shuo Gu, Yang Shen, Elaine Cheng, Fanny C.F. Ip, Xuhui Huang, Wing-Yu Fu, Nancy Y. Ip,

Neuroscience and Neuropharmacology Research

Significance Synaptic loss and dysfunction is associated with cognitive impairment in Alzheimer’s disease (AD). However, the pathophysiological mechanisms underlying synaptic impairment are largely unknown. Here, we reveal a previously unidentified signaling pathway whereby activation of a receptor tyrosine kinase EphA4 is critical for synaptic dysfunctions in AD. Proof-of-concept studies undertaken in both in vitro and in vivo systems demonstrate its importance in mediating the deficit of synaptic transmission and hippocampal long-term potentiation in AD models. Specifically, blocking the EphA4-dependent pathway through knockdown studies or the use of small-molecule inhibitors effectively rescues the impaired synaptic transmission induced by Aβ and reverses impaired synaptic plasticity in AD mouse models. Thus, this study reveals a new disease-modifying therapeutic intervention for AD.