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Article

Neurodegeneration Induced by Anti-IgLON5 Antibodies Studied in Induced Pluripotent Stem Cell-Derived Human Neurons

1
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark
2
Department of Neurology, Odense University Hospital, 5000 Odense, Denmark
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Department of Clinical Research, Odense University Hospital, 5000 Odense, Denmark
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Department of Clinical Immunology, Odense University Hospital, 5000 Odense, Denmark
5
BRIDGE—Brain Research Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark
*
Author to whom correspondence should be addressed.
Academic Editor: Andrea Pession
Cells 2021, 10(4), 837; https://doi.org/10.3390/cells10040837
Received: 22 February 2021 / Revised: 5 April 2021 / Accepted: 6 April 2021 / Published: 8 April 2021
Anti-IgLON5 disease is a progressive neurological disorder associated with autoantibodies against a neuronal cell adhesion molecule, IgLON5. In human postmortem brain tissue, the neurodegeneration and accumulation of hyperphosphorylated tau (p-tau) are found. Whether IgLON5 antibodies induce neurodegeneration or neurodegeneration provokes an immune response causing inflammation and antibody formation remains to be elucidated. We investigated the effects of anti-IgLON5 antibodies on human neurons. Human neural stem cells were differentiated for 14–48 days and exposed from Days 9 to 14 (short-term) or Days 13 to 48 (long-term) to either (i) IgG from a patient with confirmed anti-IgLON5 antibodies or (ii) IgG from healthy controls. The electrical activity of neurons was quantified using multielectrode array assays. Cultures were immunostained for β-tubulin III and p-tau and counterstained with 4′,6-Diamidine-2′-phenylindole dihydrochloride (DAPI). To study the impact on synapses, cultures were also immunostained for the synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin. A lactate dehydrogenase release assay and nuclei morphology analysis were used to assess cell viability. Cultures exposed to anti-IgLON5 antibodies showed reduced neuronal spike rate and synaptic protein content, and the proportion of neurons with degenerative appearance including p-tau (T205)-positive neurons was higher when compared to cultures exposed to control IgG. In addition, cell death was increased in cultures exposed to anti-IgLON5 IgG for 21 days. In conclusion, pathological anti-IgLON5 antibodies induce neurodegenerative changes and cell death in human neurons. This supports the hypothesis that autoantibodies may induce the neurodegenerative changes found in patients with anti-IgLON5-mediated disease. Furthermore, this study highlights the potential use of stem cell-based in vitro models for investigations of antibody-mediated diseases. As anti-IgLON5 disease is heterogeneous, more studies with different IgLON5 antibody samples tested on human neurons are needed. View Full-Text
Keywords: autoimmune encephalitis; IgLON5; phosphorylated tau; neurodegeneration autoimmune encephalitis; IgLON5; phosphorylated tau; neurodegeneration
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MDPI and ACS Style

Ryding, M.; Gamre, M.; Nissen, M.S.; Nilsson, A.C.; Okarmus, J.; Poulsen, A.A.E.; Meyer, M.; Blaabjerg, M. Neurodegeneration Induced by Anti-IgLON5 Antibodies Studied in Induced Pluripotent Stem Cell-Derived Human Neurons. Cells 2021, 10, 837. https://doi.org/10.3390/cells10040837

AMA Style

Ryding M, Gamre M, Nissen MS, Nilsson AC, Okarmus J, Poulsen AAE, Meyer M, Blaabjerg M. Neurodegeneration Induced by Anti-IgLON5 Antibodies Studied in Induced Pluripotent Stem Cell-Derived Human Neurons. Cells. 2021; 10(4):837. https://doi.org/10.3390/cells10040837

Chicago/Turabian Style

Ryding, Matias, Mattias Gamre, Mette S. Nissen, Anna C. Nilsson, Justyna Okarmus, Anne A.E. Poulsen, Morten Meyer, and Morten Blaabjerg. 2021. "Neurodegeneration Induced by Anti-IgLON5 Antibodies Studied in Induced Pluripotent Stem Cell-Derived Human Neurons" Cells 10, no. 4: 837. https://doi.org/10.3390/cells10040837

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