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

Abstract

Alzheimer's disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a smallmolecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.Abeta | receptor tyrosine kinase | ephrin | drug discovery

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

“…In vitro use of the peptide-based inhibitor of EphA4 signaling KYL [114] was shown to block Aβ-induced synaptic dysfunction, reversing both the loss of dendritic spines in cultured hippocampal neurons and the blockage of LTP induction in hippocampal slices by Aβ oligomers [110,115]. Moreover, ICV injections (~3 weeks) of KYL was shown to be effective in blocking EphA4 signaling in the hippocampus of APP/PS-1 transgenic AD mice, resulting in the complete rescue of impaired LTP normally observed in these mice [115].…”

“…Moreover, ICV injections (~3 weeks) of KYL was shown to be effective in blocking EphA4 signaling in the hippocampus of APP/PS-1 transgenic AD mice, resulting in the complete rescue of impaired LTP normally observed in these mice [115]. Finally, molecular docking studies have led to the identification of the small chemical, rhynchophylline, as a potent EphA4 signaling inhibitor, which was shown to completely block EphA4 activity in the hippocampus when administered orally (~3-4 weeks) to APP/PS-1 and Tg2576 AD mice [115]. More importantly, this treatment was able to completely restore normal synaptic plasticity in these mice, making a strong case for an EphA4-based therapeutic strategy for AD.…”

Modifications of a Nanomolar Cyclic Peptide Antagonist for the EphA4 Receptor To Achieve High Plasma Stability

“…4 Evidence in cultured neurons and mouse models has also implicated EphA4 activity in the synaptic dysfunction induced by the pathogenic amyloid-β oligomers in Alzheimer's disease. 5,6 Furthermore, EphA4 is preferentially expressed in breast cancer stem cells, where it supports malignancy by interacting with ephrin ligands expressed by monocytes/macrophages. 7 Thus, EphA4 is a promising target for promoting neural repair after injury and stroke, counteracting neurodegenerative processes, and inhibiting breast cancer malignancy.…”

“…2 Peptides appear to have greater potential than small molecules (such as rhynchophylline and bile acid derivatives) for high affinity, selective binding to the ephrinbinding pocket of EphA4 due to its broad surface and conformational flexibility. 2,6,8 Among the EphA4-targeting peptides identified using phage display screens and other strategies, the linear dodecameric KYL (KYLPYWPVLSSL) was initially considered the most promising. 2,9 Although the ephrin ligands promiscuously bind multiple Eph receptors, KYL binds only to EphA4.…”

“…[4][5][6][7]10 KYL has been administered in animal models by continuous infusion into the brain or spinal cord with minipumps. 4,6,10 However, this invasive route of administration has limited applicability in the clinic.…”