title: Blocking the Interaction between EphB2 and ADDLs by a Small Peptide Rescues Impaired Synaptic Plasticity and Memory Deficits in a Mouse Model of Alzheimer's Disease.
abstract: Soluble amyloid-β (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs), are thought to be the key pathogenic factor in Alzheimer's disease (AD), but there is still no effective treatment for preventing or reversing the progression of the disease. Targeting NMDA receptor trafficking and regulation is a new strategy for early treatment of AD. Aβ oligomers have been found to bind to the fibronectin (FN) type III repeat domain of EphB2 to trigger EphB2 degradation, thereby impairing the normal functioning of NMDA receptors and resulting in cognitive deficits. Here, we identified for the first time the interaction sites of the EphB2 FN domain with ADDLs by applying the peptide array method to design and synthesize four candidate peptides (Pep21, Pep25, Pep32, and Pep63) that might be able to block the EphB2-ADDL interaction. Among them, Pep63 was found to be the most effective at inhibiting the binding between EphB2 and ADDLs. We found that Pep63 not only rescued the ADDL-induced depletion of EphB2- and GluN2B-containing NMDA receptors from the neuronal surface in cultured hippocampal neurons, but also improved impaired memory deficits in APPswe/PS1dE9 (APP/PS1) transgenic mice and the phosphorylation and surface expression of GluN2B-containing NMDA receptors in cultures. Together, these results suggest that blocking the EphB2-ADDL interaction by small interfering peptides may be a promising strategy for AD treatment.
  
  
  
  Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and amyloid β-derived diffusible ligands (ADDLs) play a key role in triggering the early cognitive deficits that constitute AD. ADDLs may bind EphB2 and alter NMDA receptor trafficking and synaptic plasticity. Here, we identified the interaction sites of the EphB2 FN domain with ADDLs for the first time to develop a small (10 aa) peptide (Pep63) capable of blocking the EphB2-ADDL interaction. We found that Pep63 not only rescued the ADDL-induced depletion of EphB2 and GluN2B-containing NMDA receptors from the neuronal surface in cultured hippocampal neurons, but also improved impaired memory deficits in APPswe/PS1dE9 (APP/PS1) transgenic mice. Our results suggest that blocking the EphB2-ADDL interaction with Pep63 may be a promising strategy for AD treatment.
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Shi
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.|Department of Pain Medicine, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China.
authors.forename: Kai
authors.identifier: 0000-0003-0924-2121
authors.initials: K
authors.lastname: Sun
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.
authors.forename: Rui
authors.initials: R
authors.lastname: Hu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.
authors.forename: Xiao-Ya
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.
authors.forename: Qiu-Mei
authors.initials: QM
authors.lastname: Hu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.
authors.forename: Bin
authors.initials: B
authors.lastname: Yao
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.
authors.forename: Nan
authors.initials: N
authors.lastname: Sun
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Hao
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.
authors.forename: Pan
authors.initials: P
authors.lastname: Wei
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology and gaocan@xzhmu.edu.cn.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China, and.
authors.forename: Can
authors.identifier: 0000-0001-5552-9639
authors.initials: C
authors.lastname: Gao
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D018450:Disease Progression; D008024:Ligands; D008297:Male; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000503:physiopathology* / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D036183:Receptor, EphB2 / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D008024:Ligands; D010455:Peptides; C586311:Ephb2 protein, mouse; D036183:Receptor, EphB2
keywords: Alzheimer's disease; EphB2; NMDA receptor trafficking; interfering peptides; memory deficits; synaptic plasticity