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. (July 2022)

• Record Type: Journal Article
• Authors: Taniguchi, Kaori; Yamamoto, Fumiko; Amano, Akiko; Tamaoka, Akira; Sanjo, Nobuo; Yokota, Takanori; Kametani, Fuyuki; Araki, Wataru
• Is Part Of: Neuroscience research. Volume 180(2022)
• Page Start: 90
• Page End: 98
• Publication Date: 2022-07
• Subjects: Alzheimer's disease -- Amyloid-β -- Metabotropic glutamate receptor 1 -- NMDA receptor -- Oligomer -- Synapse; Neurosciences -- Research -- Periodicals; Neurosciences -- Research -- Japan -- Periodicals; Neurology -- Periodicals; Neurosciences -- Periodicals; Neurosciences -- Recherche -- Périodiques; Neurosciences -- Recherche -- Japon -- Périodiques; Neurosciences -- Research; Japan; Periodicals; 612.8
• DOI: 10.1016/j.neures.2022.03.001
• Languages: English
• ISSNs: 0168-0102

Abstract

Abstract: Recent evidence suggests that soluble amyloid-β oligomers (AβOs) act as a key factor in the pathogenetic mechanism of Alzheimer's disease (AD). AβOs 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 AβO-induced aberrations of synaptic proteins and binding of extracellular AβOs 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 AβO treatment. Double immunofluorescence staining of AβO-treated neurons without permeabilization pretreatment revealed that extracellular AβOs 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. AβO treatment altered neither total protein levels nor intracellular localizations of these receptors. These results suggest that extracellular AβOs specifically bind to both NMDA receptors containing GluN2B subunits and mGluR1. It is likely that binding of AβOs 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. Highlights: AβOs induce dislocation of both presynaptic and postsynaptic proteins in neurons. Extracellular AβOs colocalize with GluN2B-NMDARs, but not GluN2A-NMDARs. Extracellular AβOs colocalize with mGluR1 rather than mGluR5 receptors. GluN2B-NMDARs and mGluR1 likely play critical roles in the synapse pathology of AD.