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

Area of Science:

• Neuroimmunology
• Neurobiology
• Neuropathology

Background:

• Anti-IgLON5 disease is a progressive neurological disorder with sleep, gait, and movement disturbances.
• Pathology in chronic cases shows brainstem-predominant tauopathy.
• Disease is defined by antibodies against IgLON5, which impair its function in vitro.

Purpose of the Study:

• To investigate the in vivo pathogenic effects of IgLON5 antibodies through passive transfer.
• To determine if IgLON5 antibodies reduce IgLON5 clusters and cause neurological deficits in mice.

Main Methods:

• Passive transfer of CSF from anti-IgLON5 disease patients or controls into mouse ventricles.
• Assessment of motor and behavioral performance (coordination, sociability, anxiety, memory).
• Analysis of brain-bound antibodies, IgLON5 clusters, tau pathology, and neuroinflammation.

Main Results:

• Mice receiving anti-IgLON5 CSF showed impaired motor coordination and behavioral changes (reduced sociability, increased anxiety).
• Reduced total and synaptic IgLON5 clusters were observed in the hippocampus and periventricular regions.
• Microglial activation was present, but tau pathology and gliosis were absent.

Conclusions:

• Passive transfer of IgLON5 antibodies reduces neuronal IgLON5 clusters in vivo.
• This reduction is associated with microglial activation and motor/behavioral deficits.
• Results support a pathogenic role for IgLON5 antibodies in anti-IgLON5 disease.