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

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.