Abstract Anti-IgLON5 disease is an autoimmunity/neurodegeneration overlap disorder in which autoantibodies (AABs) against the neuronal cell surface protein IgLON5 lead to profound brain dysfunction. Brains of patients show Tau pathology, neuroinflammation, and neurodegeneration in multiple brain regions. Through administering patient-derived α-IgLON5 AABs to mice and cultured neurons, we here deciphered the cellular mechanisms of Tau pathology and neurodegeneration in α-IgLON5 disease, highlighting a central role of neuronal activity modulation in the disease pathology. Pathogenic human α-IgLON5 AABs induced acute neuronal hyperactivity, which triggered Tau changes typically found early in Tau-related neurodegenerative diseases like Alzheimer’s disease (AD). α-IgLON5 AAB-induced Tau phosphorylation and somatodendritic resorting selectively occurred in key hippocampal connections, involving dentate gyrus granule cells, mossy fiber projections and commissural fiber tracts. These changes were accompanied by a Tau-specific neuroinflammatory response, involving the complement pathway, microglial MHC class II proteins, T cell receptors, and deregulation of synaptic activity and cell-cell interactions. These findings provide new insights into the origin of autoimmune-triggered α-IgLON5 disease pathology and highlight that, similar to recent reports in AD patients, neuronal hyperactivity may be a disease-overarching driver of Tau pathology.

Autoimmune antibody-induced neuronal hyperactivity triggers pathological Tau in IgLON5 disease