IgLON5 autoimmune antibodies activate Tau via neuronal hyperactivity
- Bilge Askin
- Cagla Kilic
- César Cordero Gómez
- Sophie Lan-Linh Duong
- Alvaro Domingues-Baquero
- Alexander Goihl
- Karsten Nalbach
- Joana Petushi
- Pia Grundschöttel
- Jessica Wagner
- Valentine Thomas
- Janne Lamberty
- Emily Withers
- Hanna Huber
- Sabrina Huebschmann
- Ekaterina Semenova
- Paul Turko
- Andrew G. Newman
- Lisa Diez
- Marc Beyer
- Elena De Domenico
- Peter Körtvelyessy
- Dirk Reinhold
- Anja Schneider
- Jonas J. Neher
- Thomas Ulas
- Stefan F. Lichtenthaler
- Benjamin R. Rost
- Dietmar Schmitz
- Harald Prüss
- Susanne Wegmann
2026-05-13
Anti-IgLON5 disease is an autoimmune disease, in which autoantibodies (AABs) against the neuronal cell surface protein IgLON5 lead to profound brain dysfunction and Tau pathology. How α-IgLON5 AABs cause neuronal Tau protein pathology and neurodegeneration remains unclear. We find that patient-derived α-IgLON5 AABs cluster IgLON5 proteins with other cell surface proteins, leading to neuronal hyperactivity that triggers pathological Tau missorting and phosphorylation, typically observed early in Tau-related neurodegenerative diseases. In wild-type mice, α-IgLON5 AABs induce hippocampal Tau phosphorylation and neuroinflammatory responses. Our findings establish a causal link between the α-IgLON5 AABs and Tau pathology in anti-IgLON5 disease patients and highlight the role of neuronal hyperactivity as a disease-overarching driver of Tau pathology and provide a potential target for therapeutic intervention.