Home > Publications Database > Microglia actively remove NR1 autoantibody-bound NMDA receptors and associated post-synaptic proteins in neuron microglia co-cultures. > print

001     257584
005     20240112171631.0
024 7 _ |a 10.1002/glia.24369
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024 7 _ |a 0894-1491
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024 7 _ |a 1098-1136
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037 _ _ |a DZNE-2023-00460
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Rahman, Kazi Atikur
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245 _ _ |a Microglia actively remove NR1 autoantibody-bound NMDA receptors and associated post-synaptic proteins in neuron microglia co-cultures.
260 _ _ |a Bognor Regis [u.a.]
|c 2023
|b Wiley-Liss
336 7 _ |a article
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336 7 _ |a ARTICLE
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520 _ _ |a Autoantibodies against the NR1 subunit of NMDA receptors (NMDARs) have been shown to promote crosslinking and internalization of bound receptors in NMDAR encephalitis (NMDARE). This internalization-mediated loss of NMDARs is thought to be the major mechanism leading to pathogenic outcomes in patients. However, the role of bound autoantibody in engaging the resident immune cells, microglia, remains poorly understood. Here, using a patient-derived monoclonal NR1 autoantibody (hNR1-mAb) and a co-culture system of microglia and neurons, we could show that hNR1-mAb bound to hippocampal neurons led to microglia-mediated removal of hNR1-mAb bound NMDARs. These complexes were found to accumulate inside endo-lysosomal compartments of microglia. Utilizing another patient isolated monoclonal autoantibody, against the α1-subunit of GABAA receptors (α1-GABAA -mAb), such removal of receptors was found to be specific to the antibody-bound receptor targets. Interestingly, along with receptor removal, we also observed a reduction in synapse number, more specifically in the numbers of post-synaptic proteins like PSD95 and Homer 1, when microglia were present in the culture. Importantly, mutations in the Fc region of hNR1-mAb, blocking its Fcγ receptor (FcγR) and complement binding, attenuated hNR1-mAb driven loss of NMDARs and synapses, indicating that microglia engagement by bound hNR1-mAb is critical for receptor and synapse loss. Our data argues for an active involvement of microglia in removal of NMDARs and other receptors in individuals with autoimmune encephalitis, thereby contributing to the etiology of these diseases.
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650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Receptors, N-Methyl-D-Aspartate: genetics
|2 MeSH
650 _ 2 |a Receptors, N-Methyl-D-Aspartate: metabolism
|2 MeSH
650 _ 2 |a Autoantibodies: metabolism
|2 MeSH
650 _ 2 |a Coculture Techniques
|2 MeSH
650 _ 2 |a Microglia: metabolism
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a gamma-Aminobutyric Acid: metabolism
|2 MeSH
650 _ 7 |a co-culture
|2 Other
650 _ 7 |a NMDAR
|2 Other
650 _ 7 |a antibody mediated autoimmune encephalitis
|2 Other
650 _ 7 |a autoantibodies
|2 Other
650 _ 7 |a microglia, hippocampal neurons, co-culture, pre-labeling
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650 _ 7 |a hippocampal neurons
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650 _ 7 |a microglia
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650 _ 7 |a pre-labeling
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700 1 _ |a Orlando, Marta
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700 1 _ |a Boulos, Ayub
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700 1 _ |a Andrzejak, Ewa
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700 1 _ |a Schmitz, Dietmar
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700 1 _ |a Ziv, Noam E
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700 1 _ |a Prüss, Harald
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700 1 _ |a Garner, Craig C
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700 1 _ |a Ichkova, Aleksandra
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773 _ _ |a 10.1002/glia.24369
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