October 23, 2020

Investigation of anti-IgLON5-induced neurodegenerative changes in human neurons

Background: Anti-IgLON5-mediated autoimmune encephalitis is a progressive neurological disorder, associated with antibodies against a neuronal cell adhesion molecule, IgLON5. In human postmortem brain tissue neurodegeneration and accumulation of phosphorylated-Tau (p-Tau) has been found. Whether IgLON5 antibodies induce this neurodegeneration or the neurodegenerative changes provoke an immune response remains to be elucidated. Aim: To investigate the pathological effect of anti-IgLON5 antibodies on human neurons. Methods: Human neural stem cells were differentiated for 14 days, and exposed from day 9-14 to either 1) purified serum IgG from a patient with confirmed anti-IgLON5 antibodies; 2) purified serum IgG from a healthy person or 3) standard culture conditions (negative control). After fixation, cells were immunostained for neuronal ({beta}-tubulin III) and astroglial (Glial Fibrillary Acidic Protein) markers and counterstained with DAPI (nuclei). Other cultures were immunostained for p-Tau. Random images were obtained and analyzed using ImageJ software. Cell counting and a neurite outgrowth assay were performed using the Cell Counter, Analyze Particles and NeuronJ ImageJ applications. Results: The proportion of cells with a degenerative appearance (blebbing) was significantly higher for neurons exposed to anti-IgLON5 IgG when compared to IgG treated or untreated neurons. There was also a significantly higher proportion of neurons with fragmented neurites in anti-IgLON5 IgG exposed cultures compared to controls (IgG treated or untreated). Furthermore, the relative content of cells with p-Tau accumulation was higher for cultures exposed to anti-IgLON5 IgG compared to the control groups. No differences in neurite morphology and neuronal or astroglial cell death were detected. Conclusions: Pathological anti-IgLON5 antibodies induce neurodegenerative changes in human neurons along with increased accumulation of p-Tau. The findings support the hypothesis that these antibodies are causative for the neurodegenerative changes found in patients with anti-IgLON5-mediated autoimmune encephalitis.

 bioRxiv Subject Collection: Neuroscience

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