257584 20240112171631.0 10.1002/glia.24369 doi pmid:37026600 pmid 0894-1491 ISSN 1098-1136 ISSN altmetric:145398054 altmetric DZNE-2023-00460 English 610 Rahman, Kazi Atikur P:(DE-HGF)0 0 Microglia actively remove NR1 autoantibody-bound NMDA receptors and associated post-synaptic proteins in neuron microglia co-cultures. Bognor Regis [u.a.] 2023 Wiley-Liss article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1687164890_9363 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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. 351 - Brain Function (POF4-351) G:(DE-HGF)POF4-351 POF4-351 POF IV 0 353 - Clinical and Health Care Research (POF4-353) G:(DE-HGF)POF4-353 POF4-353 POF IV 1 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de Humans MeSH Receptors, N-Methyl-D-Aspartate: genetics MeSH Receptors, N-Methyl-D-Aspartate: metabolism MeSH Autoantibodies: metabolism MeSH Coculture Techniques MeSH Microglia: metabolism MeSH Neurons: metabolism MeSH gamma-Aminobutyric Acid: metabolism MeSH co-culture Other NMDAR Other antibody mediated autoimmune encephalitis Other autoantibodies Other microglia, hippocampal neurons, co-culture, pre-labeling Other hippocampal neurons Other microglia Other pre-labeling Other Receptors, N-Methyl-D-Aspartate NLM Chemicals Autoantibodies NLM Chemicals gamma-Aminobutyric Acid 56-12-2 NLM Chemicals Orlando, Marta 1 Boulos, Ayub 2 Andrzejak, Ewa P:(DE-2719)2811708 3 dzne Schmitz, Dietmar P:(DE-2719)2810725 4 dzne Ziv, Noam E 5 Prüss, Harald P:(DE-2719)2810931 6 dzne Garner, Craig C P:(DE-2719)2810922 7 dzne Ichkova, Aleksandra P:(DE-2719)9000590 8 Last author dzne 10.1002/glia.24369 p. glia.24369 PERI:(DE-600)1474828-9 8 1804-1829 Glia 71 2023 0894-1491 https://onlinelibrary.wiley.com/doi/10.1002/glia.24369 http://pub.dzne.de/record/257584/files/DZNE-2023-00460%20SUP.zip http://pub.dzne.de/record/257584/files/DZNE-2023-00460.pdf OpenAccess http://pub.dzne.de/record/257584/files/DZNE-2023-00460.pdf?subformat=pdfa pdfa OpenAccess oai:pub.dzne.de:257584 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 3 P:(DE-2719)2811708 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 4 P:(DE-2719)2810725 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 6 P:(DE-2719)2810931 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 7 P:(DE-2719)2810922 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 8 P:(DE-2719)9000590 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-351 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Brain Function 0 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-353 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Clinical and Health Care Research 1 2023 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2022-11-08 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2022-11-08 Creative Commons Attribution-NonCommercial CC BY-NC 4.0 LIC:(DE-HGF)CCBYNC4 HGFVOC DEAL Wiley StatID:(DE-HGF)3001 StatID 2022-11-08 ger WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2022-11-08 OpenAccess StatID:(DE-HGF)0510 StatID Nationallizenz StatID:(DE-HGF)0420 StatID 2023-08-24 ger DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2023-08-24 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2023-08-24 DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2023-08-24 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2023-08-24 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2023-08-24 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2023-08-24 JCR StatID:(DE-HGF)0100 StatID GLIA : 2022 2023-08-24 IF >= 5 StatID:(DE-HGF)9905 StatID GLIA : 2022 2023-08-24 I:(DE-2719)1810001 AG Garner Synaptopathy 0 I:(DE-2719)1810004 AG Schmitz 1 ; AG Schmitz Network Dysfunction 1 I:(DE-2719)1810003 AG Prüß Autoimmune Enzephalopathies 2 journal VDB I:(DE-2719)1810001 I:(DE-2719)1810004 I:(DE-2719)1810003 UNRESTRICTED FullTexts