Academic Journal
Establishment of a passive-transfer mouse model of anti-NMDAR encephalitis and delineation of the PI3K-AKT-HIF-1α Axis in antibody-induced neuronal injury.
| Τίτλος: | Establishment of a passive-transfer mouse model of anti-NMDAR encephalitis and delineation of the PI3K-AKT-HIF-1α Axis in antibody-induced neuronal injury. |
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| Συγγραφείς: | Li H; Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, Guangdong Province, China., Zhang S; Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China., Shu Y; Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, Guangdong Province, China., Zhao Y; Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, Guangdong Province, China., Qiu W; Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, Guangdong Province, China., Long Y; Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China., Wang Y; Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou 510630, Guangdong Province, China. Electronic address: wangyuge@mail.sysu.edu.cn. |
| Πηγή: | Journal of neuroimmunology [J Neuroimmunol] 2026 Aug; Vol. 417, pp. 578943. Date of Electronic Publication: 2026 Apr 21. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier/North-Holland Country of Publication: Netherlands NLM ID: 8109498 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-8421 (Electronic) Linking ISSN: 01655728 NLM ISO Abbreviation: J Neuroimmunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Amsterdam] : Elsevier/North-Holland, c1981- |
| Ιατρικοί όροι (MeSH): | Hypoxia-Inducible Factor 1, alpha Subunit*/metabolism , Proto-Oncogene Proteins c-akt*/metabolism , Phosphatidylinositol 3-Kinases*/metabolism , Neurons*/metabolism , Neurons*/pathology , Neurons*/drug effects , Anti-N-Methyl-D-Aspartate Receptor Encephalitis*/immunology , Anti-N-Methyl-D-Aspartate Receptor Encephalitis*/metabolism , Anti-N-Methyl-D-Aspartate Receptor Encephalitis*/pathology , Immunization, Passive*/methods , Disease Models, Animal* , Autoantibodies*, Signal Transduction/physiology ; Hippocampus/pathology ; Hippocampus/metabolism ; Animals ; Mice ; Humans ; Male ; Female ; Mice, Inbred C57BL ; Immunoglobulin G |
| Περίληψη: | Background and Objective: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis. Currently, the development of its animal models lacks maturity and efficiency. This study aimed to establish a reliable and efficient mouse model of anti-NMDAR encephalitis and to investigate the pathological mechanisms. Methods: Immunoadsorption eluates were collected from three patients with anti-NMDAR encephalitis and three control patients. Immunoglobulin G (IgG) was purified from these eluates. A passive transfer mouse model was established by injecting the IgG into the hippocampal region of mice. RNA sequencing was performed on IgG treated neurons in vitro. And the role of the PI3K-AKT-HIF-1α signaling axis in NMDAR-IgG-induced neuronal injury was validated. Results: Compared with control-IgG, injection of NMDAR-IgG resulted in detectable antibody binding to hippocampal neurons in brain at 7 days post-injection, accompanied by loss of the postsynaptic scaffolding protein. Behavioral assessments revealed that NMDAR-IgG-treated mice exhibited cognitive impairment, depressive-like and despair-like behaviors on day 7, which had resolved by day 14. RNA sequencing of NMDAR-IgG-treated neurons in vitro identified dysregulation of the PI3K-AKT-HIF-1α signaling axis. Western blot demonstrated activation of this signaling axis in neurons following NMDAR-IgG treatment in both in vivo and in vitro. Additional experiments demonstrated that this signaling axis constitutes a critical pathway mediating NMDAR-IgG-induced neuronal injury. Finally, RNA sequencing and immunofluorescence confirmed microglial activation and increased HIF-1α secretion in the brains of NMDAR-IgG-treated mice. Conclusion: We established a mouse model of anti-NMDAR encephalitis using antibodies purified from human immunoadsorption eluates. Furthermore, our findings demonstrate that the PI3K-AKT-HIF-1α signaling axis serves as a molecular pathway mediating NMDAR-IgG-induced neuronal injury. (Copyright © 2024. Published by Elsevier B.V.) |
| Competing Interests: | Declaration of competing interest The authors have declared that no competing interests exist. |
| Contributed Indexing: | Keywords: Autoimmune encephalitis; Microglia; N-methyl-d-aspartate receptor; Passive immunization |
| Substance Nomenclature: | 0 (Hypoxia-Inducible Factor 1, alpha Subunit) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) EC 2.7.1.- (Phosphatidylinositol 3-Kinases) 0 (Hif1a protein, mouse) 0 (Autoantibodies) 0 (Immunoglobulin G) 0 (HIF1A protein, human) |
| Entry Date(s): | Date Created: 20260428 Date Completed: 20260715 Latest Revision: 20260715 |
| Update Code: | 20260716 |
| DOI: | 10.1016/j.jneuroim.2026.578943 |
| PMID: | 42048740 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1872-8421 |
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| DOI: | 10.1016/j.jneuroim.2026.578943 |