Amyloid-β oligomers interact with NMDA receptors containing GluN2B subunits and metabotropic glutamate receptor 1 in primary cortical neurons: Relevance to the synapse pathology of Alzheimer's disease

Recent evidence suggests that soluble amyloid-beta oligomers (A beta Os) act as a key factor in the pathogenetic mechanism of Alzheimer's disease (AD). A beta Os induce neurotoxic and synaptotoxic effects probably through binding to certain receptors, however it remains unclarified which receptors are most critically involved. In addition, dysregulation in glutamatergic signaling is implicated in AD. In this study, we used a rat primary cortical neuron model to investigate A beta O-induced aberrations of synaptic proteins and binding of extracellular A beta Os to candidate receptors in the glutamatergic system. Immunocytochemical analyses showed that both presynaptic (SNAP-25, synapsin I) and postsynaptic (spinophilin, homer 1b/c) proteins appeared to aberrantly dislocate from synapses upon A beta O treatment. Double immunofluorescence staining of A beta O-treated neurons without permeabilization pretreatment revealed that extracellular A beta Os exist over neuronal soma and neurites and clearly colocalized with GluN1 and GluN2B subunits of NMDA receptors and metabotropic glutamate receptor 1 (mGluR1), but not with NMDA GluN2A subunits and mGluR5. A beta O treatment altered neither total protein levels nor intracellular localizations of these receptors. These results suggest that extracellular A beta Os specifically bind to both NMDA receptors containing GluN2B subunits and mGluR1. It is likely that binding of A beta Os to these receptors induces various pathological responses, consequently leading to synaptic disruptions. Our study thus highlights the important roles of GluN2B-containing NMDA receptors and mGluR1 receptors in the synapse pathology in AD.

Automated summary

Recent evidence suggests that soluble amyloid-beta oligomers (AβOs) play a key role in the development of Alzheimer's disease (AD). AβOs induce neurotoxic and synaptotoxic effects by binding to certain receptors, specifically the GluN2B subunits of NMDA receptors and mGluR1. This study highlights the significance of these receptors in synaptic pathology in AD.