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-␤ (A␤) oligomers, also known as A␤-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. A␤ 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.

Physico-Pathologic Mechanisms Involved in Neurodegeneration: Misfolded Protein-Plasma Membrane Interactions

“…Small peptides reproducing this interface prevented Ab assemblies from interacting with a3-NKA and were shown to be neuroprotective in a preliminary in vitro study (Ohnishi et al, 2015). Similarly, small peptides preventing Ab binding to EphB2 rescued the impaired synaptic plasticity and memory deficits in a mouse model of AD by modulating NMDA receptors (Shi et al, 2016). This suggests that the peptides may have acted as a decoy to lure Ab aggregates away from interacting membrane receptors and emphasizes the therapeutic potential of targeting specific interfaces between pathogenic protein aggregates and their membrane protein partners.…”

The Dual Role of Glutamatergic Neurotransmission in Alzheimer’s Disease: From Pathophysiology to Pharmacotherapy

“…Aβ oligomers also seem to bind the surface tyrosine kinase receptor namely the Ephrin ligand-receptor (EphB2), which maintains the integrity of NMDA receptors. Loss of NMDA receptor functions and reduction in LTP are noticed after EphB2 degradation that resulted in a decrease in NMDA receptor surface localization [ 135 ]. AD mouse models and post-mortem analysis of the prefrontal cortex in AD patients displayed an increase in expression of striatal-enriched protein tyrosine phosphatase 61 (STEP61).…”

Kalirin‐7 prevents dendritic spine dysgenesis induced by amyloid beta‐derived oligomers

“…Kalirin‐7 is also phosphorylated by EphB2, which leads to a clustering of kalirin‐7 in the synapse and is required for ephrinB‐induced spine formation (Penzes et al., ). Aβ oligomers have been shown to bind EphB2 in cultured hippocampal neurons, leading to its degradation (Lacor et al., ; Shi et al., ). Conversely, overexpression of EphB2 in the hippocampus of AD model mice is capable of preventing the loss of NMDA receptors and cognitive deficits caused by excess Aβ 1‐42 exposure (Cisse et al., ; Hu et al., ; Miyamoto, Kim, Knox, Johnson, & Mucke, ).…”