PASSIVE TRANSFER OF HUMAN IGLON5 ANTIBODIES DECREASES NEURONAL IGLON5 CLUSTERS AND INDUCES MOTOR DYSFUNCTION IN MICE

Anti-IgLON5 disease is a progressive neurological condition characterized by sleep parasomnias, apneas, stridor, gait instability, and bulbar symptoms. The diagnostic hallmark is the presence of antibodies against IgLON5 (IgLON5-abs), a neuronal cell adhesion molecule of unknown function. In vitro studies indicate that IgLON5-abs decreases IgLON5 membrane clustering and disrupts the neuronal cytoskeleton. However, it remains unclear whether these effects can be reproduced in vivo via passive antibody transfer.
We developed a passive transfer model by infusing cerebrospinal fluid (CSF) from patients with anti-IgLON5 disease or controls into the brains of adult mice over 14 days via osmotic pumps. Behavioral assessments evaluated motor coordination, sociability, anxiety-like behavior, and spatial memory. Mice were sacrificed on Days 7, 18, and 30 to detect brain-bound human antibodies and quantify total and synaptic IgLON5 clusters by confocal microscopy.
In mice receiving CSF with IgLON5-abs, but not in controls, human IgG deposition was primarily localized to the hippocampus and periventricular regions, coinciding with a reduction in both total and synaptic IgLON5 clusters, whereas levels of the postsynaptic marker PSD95 remained unchanged. The decrease in IgLON5 clusters persisted through Day 30. Mice infused with IgLON5-abs showed impaired motor coordination, reduced social interaction, increased anxiety and depressed-like behavior and weight loss. The brain of mice that received IgLON5-abs showed microglial activation without evidence of tau pathology.
This model demonstrates in vivo that IgLON5-abs, reduce IgLON5 clusters, as observed in vitro, and trigger microglial activation. These results support the role of IgLON5-abs in anti-IgLON5 disease pathogenesis.