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

Abstract

Anti-IgLON5 disease is a progressive neurological disorder, associated with autoantibodies against a neuronal cell adhesion molecule, IgLON5. In human post-mortem brain tissue neurodegeneration and accumulation of phosphorylated-Tau is found. Whether IgLON5 antibodies induce neurodegeneration or neurodegeneration provokes an immune response remains to be elucidated. To clarify this, we exposed human stem cell derived neurons to patient anti-IgLON5 antibodies. Human neural stem cells were differentiated for 14-48 days, and exposed from day 9-14, or day 13-48 to either 1) IgG from a patient with confirmed anti-IgLON5 antibodies; 2) IgG from a healthy person or left untreated. Electrical neuronal activity was quantified using a multi electrode array. Cultures were immunostained for {beta}-tubulin III, phosphorylated-Tau and counterstained with DAPI. Other cultures were immunostained for synaptic proteins PSD95 and synaptophysin. Lactate dehydrogenase release and nuclei morphology analyses were performed to assess cell viability. Spike rates and quantity of synaptic clusters were significantly reduced in anti-IgLON5 exposed cultures, and the proportion of cells with degenerative appearance was significantly higher for the anti-IgLON5 IgG group. Furthermore, the content of cells displaying accumulation of phosphorylated-Tau was higher for anti-IgLON5 exposed cultures. After five weeks, cultures exposed to anti-IgLON5 IgG contained significantly more dying cells. In conclusion, exposure of human neurons to pathological anti-IgLON5 antibodies cause functional impairment, synaptic and neurodegenerative changes, ultimately leading to cell death. This supports autoantibodies as a causative factor responsible for the neurodegenerative changes seen in patients with anti-IgLON5 disease and mimics pathological observations.