Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood–brain barrier integrity
Abstract
In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable…
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Transgenic mice lacking Apoe develop an early BBB breakdown.
“Transgenic mice lacking Apoe also develop an early BBB breakdown (60, 99, 147, 187, 226, 233, 406, 426, 437, 554), indicating that APOE is essential for maintaining BBB integrity.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [233]
Cites
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies
Dalmau, J., Gleichman, A. J., Hughes, E. G., Rossi, J. E., Peng, X., Lai, M., Dessain, S. K., Rosenfeld, M. R., Balice-Gordon, R., & Lynch, D. R. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70224-2 · Cited by 3,488 · see citing works
Titulaer, M. J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., Honig, L. S., Benseler, S. M., Kawachi, I., Martinez-Hernandez, E., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70310-1 · Cited by 3,165 · see citing works
Dalmau, J., Tüzün, E., Wu, H., Masjuan, J., Rossi, J. E., Voloschin, A., Baehring, J. M., Shimazaki, H., Koide, R., King, D., et al. (2007) · Annals of Neurology · doi:10.1002/ana.21050 · Cited by 2,492 · see citing works
Visscher, P. M., Brown, M. A., McCarthy, M. I., & Yang, J. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.11.029 · Cited by 2,425 · see citing works
Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. (2012) · Nature · doi:10.1038/nature11087 · Cited by 1,293 · see citing works
NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders
Lau, C. G., & Zukin, R. S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2153 · Cited by 1,159 · see citing works
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Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,294 · see citing works
Establishment and Dysfunction of the Blood-Brain Barrier
Zhao, Z., Nelson, A. R., Betsholtz, C., & Zlokovic, B. V. (2015) · Cell · doi:10.1016/j.cell.2015.10.067 · Cited by 1,670 · see citing works
Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels
Hansen, K. B., Wollmuth, L. P., Bowie, D., Furukawa, H., Menniti, F. S., Sobolevsky, A. I., Swanson, G. T., Swanger, S. A., Greger, I. H., Nakagawa, T., et al. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000131 · Cited by 686 · see citing works
Alzheimer’s disease: A matter of blood–brain barrier dysfunction?
Montagne, A., Zhao, Z., & Zlokovic, B. V. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20171406 · Cited by 672 · see citing works
Psychiatric comorbidities in epilepsy.
Josephson, C. B., & Jetté, N. (2017) · International Review of Psychiatry · doi:10.1080/09540261.2017.1302412 · Cited by 224 · see citing works
Kępińska, A. P., Iyegbe, C. O., Vernon, A. C., Yolken, R., Murray, R. M., & Pollak, T. A. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00072 · Cited by 193 · see citing works
Cerebrospinal Fluid Biomarkers of Neurovascular Dysfunction in Mild Dementia and Alzheimer'S Disease
Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2015.76 · Cited by 122 · see citing works
Platt, M. P., Agalliu, D., & Cutforth, T. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00442 · Cited by 108 · see citing works
Microglia ablation alleviates myelin-associated catatonic signs in mice
Janova, H., Arinrad, S., Balmuth, E., Mitjans, M., Hertel, J., Habes, M., Bittner, R. A., Pan, H., Goebbels, S., Begemann, M., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci97032 · Cited by 107 · see citing works
Self-citationWesselingh, R., Butzkueven, H., Buzzard, K., Tarlinton, D., O'Brien, T. J., & Monif, M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02066 · Cited by 83 · see citing works
Lepeta, K., Purzycka, K. J., Pachulska‐Wieczorek, K., Mitjans, M., Begemann, M., Vafadari, B., Bijata, K., Adamiak, R. W., Ehrenreich, H., Dziembowska, M., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201707723 · Cited by 39 · see citing works
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- Authors
- Hammer, C., Stepniak, B., Schneider, A., Papiol, S., Tantra, M., Begemann, M., Sirén, A.-L., Pardo, L. A., Sperling, S., Mohd Jofrry, S., Gurvich, A., Jensen, N., Ostmeier, K., Lühder, F., Probst, C., Martens, H., Gillis, M., Saher, G., Assogna, F., Spalletta, G., Stöcker, W., Schulz, T. F., Nave, K.-A., & Ehrenreich, H.
- Affiliations
- Max Planck Institute of Experimental Medicine (DE)
- German Center for Neurodegenerative Diseases (DE)
- Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103 (DE)
- Universitätsklinikum Würzburg (DE)
- Universitätsmedizin Göttingen (DE)
- Medizinische Hochschule Hannover (DE)
- Fondazione Santa Lucia (IT)
- Corresponding author
- Ehrenreich, H
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2013-09-03
- Volume
- 19
- Issue
- 10
- Pages
- 1143-1149
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2029974888
- Cited by
- 342
- References
- 7
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 12 · 2023: 19 · 2022: 29 · 2021: 46 · 2020: 25 · 2019: 26 · 2018: 23 · 2017: 43 · 2016: 31 · 2015: 32 · 2014: 28 · 2013: 4
- FWCI
- 20.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- DZNE Pub (submittedVersion)
- GRO (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Keywords
- blood-brain barrier integrity, schizophrenia, seroprevalence, ApoE-deficient mice, influenza, genetic susceptibility, neurotrauma, childbirth complications, NMDA receptor 1, autoimmunity, neuropsychiatric disorders
- MeSH terms
- Adult, Aged, Animals, Apolipoproteins E, Autoantibodies, Blood-Brain Barrier, Cerebral Cortex, Endocytosis, Female, Humans, Influenza, Human, Male, Mice, Inbred C57BL, Middle Aged, Neurons, Parkinson Disease, Schizophrenia, Receptors, N-Methyl-D-Aspartate, Mice, Knockout, Mood Disorders, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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