Overexpression of EphB2 in hippocampus rescues impaired NMDA receptors trafficking and cognitive dysfunction in Alzheimer model

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease, which affects more and more people. But there is still no effective treatment for preventing or reversing the progression of the disease. Soluble amyloid-beta (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs) play an important role in AD. Synaptic activity and cognition critically depend on the function of glutamate receptors. Targeting N-methyl-D-aspartic acid (NMDA) receptors trafficking and its regulation is a new strategy for AD early treatment. EphB2 is a key regulator of synaptic localization of NMDA receptors. Aβ oligomers could bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. Here we identified that overexpression of EphB2 with lentiviral vectors in dorsal hippocampus improved impaired memory deficits and anxiety or depression-like behaviors in APPswe/PS1-dE9 (APP/PS1) transgenic mice. Phosphorylation and surface expression of GluN2B-containing NMDA receptors were also improved. Overexpression of EphB2 also rescued the ADDLs-induced depletion of the expression of EphB2 and GluN2B-containing NMDA receptors trafficking in cultured hippocampal neurons. These results suggest that improving the decreased expression of EphB2 and subsequent GluN2B-containing NMDA receptors trafficking in hippocampus may be a promising strategy for AD treatment.

Linkage analysis of multiplex Caribbean Hispanic families loaded for unexplained early‐onset cases identifies novel Alzheimer's disease loci

“…Increasing EphB2 levels in a mouse model of AD improves memory deficits, phosphorylation, and surface expression of GluN2B-containing NMDA receptors [40] , [41] , [42] . Overexpression of EphB2 also rescues the Aβ-derived diffusible ligands–induced depletion of the expression of EphB2 and GluN2B-containing NMDA receptors trafficking in cultured hippocampal neurons [41] . These results suggest that improving the decreased expression of EphB2 and subsequent GluN2B-containing NMDA receptors trafficking in the hippocampus may be a promising strategy for AD treatment.…”

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

“…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, ). Kalirin‐7 directly interfaces with NMDA receptors, and this interaction is critical for synaptic plasticity (Kiraly, Lemtiri‐Chilieh, Levine, Mains, & Eipper, ).…”

Ca2+homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles

“…which is paradoxical to the subunit theory [for more debate, see review in Parsons et al (104)]. The receptor tyrosine kinase EphB2 promotes the synaptic localization of GluN2B NMDAR in mature neurons (105), whose degeneration is induced by Ab oligomers (106). Enhancing the expression of EphB2 with hippocampal Lenti-EphB2 treatment rescues the surface trafficking of GluN2B NMDAR and improves the learning and memory function in APP/ PS1 Tg mice (106).…”

“…The receptor tyrosine kinase EphB2 promotes the synaptic localization of GluN2B NMDAR in mature neurons (105), whose degeneration is induced by Ab oligomers (106). Enhancing the expression of EphB2 with hippocampal Lenti-EphB2 treatment rescues the surface trafficking of GluN2B NMDAR and improves the learning and memory function in APP/ PS1 Tg mice (106). These results suggest that GluN2B NMDAR is more than a simplex death receptor, and the synaptic-located GluN2B NMDAR may play a crucial neuroprotective role.…”