Human IgLON5 Antibodies Reduce Neuronal IgLON5 Clusters and Cause Motor Dysfunction in Mice

Anti-IgLON5 disease is a progressive neurologic disorder characterized by sleep disturbances, gait instability, involuntary movements, and bulbar dysfunction. In long-standing cases, autopsy studies reveal a brainstem-predominant neuronal tauopathy. The disease is defined by antibodies against the neuronal adhesion molecule IgLON5 (IgLON5-abs), which reduce IgLON5 membrane clusters and disrupt the cytoskeleton in vitro. Our aim was to investigate whether these pathogenic effects occur in vivo through passive antibody transfer.

A passive transfer model was established by infusing CSF from patients with anti-IgLON5 disease or controls into the lateral ventricles of adult mice for 14 days via osmotic pumps. Motor and behavioral performance was evaluated using tests of coordination, sociability, anxiety-like behavior, and spatial memory. Mice were sacrificed at days 7, 18, and 30 for analysis of brain-bound human antibodies and quantification of total and synaptic IgLON5 clusters by confocal microscopy. Additional analyses included immunohistochemistry for phosphorylated tau, gliosis, and microglial activation.

Mice receiving anti-IgLON5 CSF exhibited impaired motor coordination in the beam-walking and rotarod performance. Behavioral alterations included reduced social interaction, increased anxiety-like behavior, weight loss, and increased liquid intake. Human IgG deposition was predominantly localized in the hippocampus and periventricular regions, coinciding with a reduction in total and synaptic IgLON5 clusters whereas levels of the postsynaptic marker PSD95 remained unchanged. The reduction in IgLON5 clusters persisted through day 30. Microglial activation was consistently observed in affected regions, but tau pathology and gliosis were absent.

This passive transfer model demonstrates that IgLON5 antibodies reduce neuronal membrane IgLON5 clusters, accompanied by microglial activation and motor and behavioral alterations. These results support a pathogenic role of IgLON5 antibodies in anti-IgLON5 disease.