Alterations of <scp>NMDAR</scp> Subunits in the Cerebrospinal Fluid Across Neurodegenerative and Immunological Disorders
N-methyl-D-aspartate receptors (NMDARs) are glutamate-binding calcium channels that play a key role in brain function and have been linked to many neurological disorders. NMDARs are multi-pass membrane heterotetrameric complexes composed of two compulsory GluN1 subunits and two GluN2 (A-D) or GluN3 (A-B) subunits, from which GluN1, GluN2B, GluN2A, and GluN3A are widely expressed in the adult brain. This study assesses the presence of GluN1, GluN2B, GluN2A, and GluN3A in the cerebrospinal fluid (CSF) from healthy individuals, viral and autoimmune encephalitis, Huntington's disease (HD) and Alzheimer's disease (AD) patients. Samples were run in SDS-PAGE under reducing conditions and resolved with different anti-ectodomain and anti-C-terminal antibodies that combined with immunoprecipitation analyses, served to demonstrate the presence of full-length GluN1, GluN2A, GluN2B, and GluN3A in CSF. These NMDAR subunit complexes are not associated with extracellular vesicles. As a proof of concept of the identity of NMDAR subunits in the CSF, we demonstrated reduced levels of GluN1 in the CSF from patients with autoimmune encephalitis caused by anti-GluN1 antibodies compared with other causes of encephalitis; and showed a depletion of CSF GluN3A in a Grin3a knockout mouse model. Moreover, we observed higher GluN3A levels in CSF in both asymptomatic and symptomatic HD patients; while GluN2A levels were lower in CSF from AD patients. In conclusion, here we demonstrate the presence of NMDAR full-length subunits in CSF and that changes in NMDAR subunits balance could serve to identify alterations related to pathological conditions.
Authors
- Rocío Pérez‐González (ORCID: https://orcid.org/0000-0002-0641-2001)
- Javier Sáez‐Valero (ORCID: https://orcid.org/0000-0001-7480-320X)
- Gunnar Brinkmalm (ORCID: https://orcid.org/0000-0001-6958-2393)
- Jesús Pérez‐Pérez (ORCID: https://orcid.org/0000-0002-9835-0484)
- Davide Arici
- Chiara Tolassi (ORCID: https://orcid.org/0009-0006-8741-1313)
- Elena Camporesi (ORCID: https://orcid.org/0000-0003-1044-0192)
- Irene Volonghi (ORCID: https://orcid.org/0000-0002-6864-1475)
- Sergio Escamilla (ORCID: https://orcid.org/0000-0003-0952-7506)
- Jaime Kulisevsky (ORCID: https://orcid.org/0000-0003-4870-1431)
- Henrik Zetterberg (ORCID: https://orcid.org/0000-0003-3930-4354)
- Alessandro Padovani (ORCID: https://orcid.org/0000-0002-0119-3639)
- Inmaculada Cuchillo‐Ibáñez (ORCID: https://orcid.org/0000-0002-3689-5518)
- Andrea Pilotto
- Kaj Blennow
- Carmen Márquez‐Marco
Institutions
- Universitat Autònoma de Barcelona (ES)
- University of Science and Technology of China (CN)
- Sahlgrenska University Hospital (SE)
- Hospital de Sant Pau (ES)
- Sorbonne Université (FR)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Instituto de Neurociencias (ES)
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
- Huntington's Disease Association (GB)
- Institute for Neurodegenerative Disorders (US)
- Pitié-Salpêtrière Hospital (FR)
- UK Dementia Research Institute (GB)
- MRC Prion Unit (GB)
- Biomedical Research Institute (US)
- Institut du Cerveau (FR)
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL) (ES)
- University College London (GB)
- University of Brescia (IT)
- University of Gothenburg (SE)
Publication Details
- Journal
- Journal of Neurochemistry
- Published
- 2025-08-01
- DOI
- https://doi.org/10.1111/jnc.70192
- Citations
- 2
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- University of South Carolina
- Ministero della Salute
- Generalitat Valenciana
- Universidade de Coimbra
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- UK Dementia Research Institute
- Horizon 2020 Framework Programme
- Instituto de Salud Carlos III
- European Regional Development Fund