IgLON5 autoimmune antibodies activate Tau via neuronal hyperactivity
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.
Authors
- Sabrina Huebschmann
- Hanna Huber (ORCID: https://orcid.org/0009-0004-3080-6870)
- Alexander Goihl (ORCID: https://orcid.org/0000-0002-8652-5136)
- Jonas J. Neher (ORCID: https://orcid.org/0000-0003-1346-8924)
- Lisa Diez (ORCID: https://orcid.org/0000-0003-3101-0191)
- Paul Turko (ORCID: https://orcid.org/0000-0002-1305-6711)
- Dirk Reinhold (ORCID: https://orcid.org/0000-0002-6441-9631)
- Karsten Nalbach (ORCID: https://orcid.org/0000-0002-3928-4026)
- Stefan F. Lichtenthaler (ORCID: https://orcid.org/0000-0003-2211-2575)
- Andrew G. Newman (ORCID: https://orcid.org/0000-0002-0222-9162)
- Sophie Lan-Linh Duong
- Dietmar Schmitz (ORCID: https://orcid.org/0000-0003-2741-5241)
- Bilge Askin (ORCID: https://orcid.org/0000-0002-6582-3249)
- Cagla Kilic
- Janne Lamberty
- Valentine Thomas
- Marc Beyer
- Pia Grundschöttel
- Jessica Wagner (ORCID: https://orcid.org/0009-0004-8585-6998)
- Elena De Domenico (ORCID: https://orcid.org/0000-0003-0336-8284)
- Peter Körtvelyessy (ORCID: https://orcid.org/0000-0003-1262-6169)
- Thomas Ulas (ORCID: https://orcid.org/0000-0002-9785-4197)
- Emily Withers (ORCID: https://orcid.org/0009-0003-1619-8541)
- Ekaterina Semenova
- Anja Schneider (ORCID: https://orcid.org/0000-0001-9540-8700)
- Joana Petushi (ORCID: https://orcid.org/0009-0003-5359-2126)
- Benjamin R. Rost (ORCID: https://orcid.org/0000-0003-1906-0081)
- César Cordero Gómez
- Alvaro Domingues-Baquero
- Harald Prüss (ORCID: https://orcid.org/0000-0002-8283-7976)
- Susanne Wegmann (ORCID: https://orcid.org/0000-0002-5388-2479)
Institutions
- University of Bonn (DE)
- German Center for Neurodegenerative Diseases (DE)
- TUM Klinikum (DE)
- Munich Cluster for Systems Neurology (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Einstein Center for Neurosciences Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
- Ludwig-Maximilians-Universität München (DE)
- Epigenomics (Germany) (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2026-05-13
- DOI
- https://doi.org/10.1126/sciadv.aec2042
- Primary Topic
- Autoimmune Neurological Disorders and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Helmholtz-Gemeinschaft
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Einstein Stiftung Berlin