Peer-reviewedCC BYScience Advances
IgLON5 autoimmune antibodies activate Tau via neuronal hyperactivity
16 affiliations
- 1Einstein Center for Neurosciences (ECN), Charité – Universitätsmedizin Berlin; Berlin, Germany
- 2German Center for Neurodegenerative Diseases (DZNE); Berlin, Germany
- 3Department of Neurology and Experimental Neurology, Charité – Universitätsmedizin Berlin; Berlin, Germany
- 4Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin; Berlin, Germany
- 5Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University; Magdeburg, Germany
- 6German Center for Neurodegenerative Diseases (DZNE); Munich, Germany
- 7Munich Cluster for Systems Neurology (SyNergy); Munich, Germany
- 8Neuroproteomics, School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich; Munich, Germany
- 9Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn; Bonn, Germany
- 10German Center for Neurodegenerative Diseases (DZNE); Bonn, Germany
- 11Platform for Single Cell Genomics and Epigenomics (PRECISE) at the German Center for Neurodegenerative Diseases and the University of Bonn; Bonn, Germany
- 12Metabolic Biochemistry, Biomedical Center Munich (BMC), Faculty of Medicine, Ludwig Maximilian University; Munich, Germany
- 13Institute of Integrative Neuroanatomy, Charité; Berlin, Germany
- 14Institute of Cell Biology and Neurobiology, Charité – Universitätsmedizin Berlin; Berlin, Germany
- 15German Center for Neurodegenerative Diseases (DZNE); Magdeburg, Germany
- 16Neuroscience Research Center (NWFZ), Charité-Universitätsmedizin; Berlin, Germany
Abstract
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.
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BibTeX
@article{askin2026iglon5,
title = {{IgLON5 autoimmune antibodies activate Tau via neuronal hyperactivity}},
author = {Bilge Askin and Cagla Kilic and César Cordero Gómez and Sophie Lan-Linh Duong and Alvaro Dominguez‐Baquero and Alexander Goihl and Karsten Nalbach and Joana Petushi and Pia Grundschöttel and Jessica Wagner and Valentine Thomas and Janne Lamberty and Emily Withers and Hanna Huber and Sabrina Hübschmann and Ekaterina Semenova and Paul Turko and Andrew G. Newman and Lisa Diez and Marc Beyer and Elena De Domenico and Péter Körtvelyessy and Dirk Reinhold and Anja Schneider and Jonas J. Neher and T Ulas and Stefan F. Lichtenthaler and Benjamin R. Rost and Dietmar Schmitz and Harald Prüß and Susanne Wegmann},
journal = {Science Advances},
year = {2026},
month = may,
doi = {10.1126/sciadv.aec2042},
url = {https://doi.org/10.1126/sciadv.aec2042},
note = {CC BY},
}
RIS
TY - JOUR
TI - IgLON5 autoimmune antibodies activate Tau via neuronal hyperactivity
AU - Bilge Askin
AU - Cagla Kilic
AU - César Cordero Gómez
AU - Sophie Lan-Linh Duong
AU - Alvaro Dominguez‐Baquero
AU - Alexander Goihl
AU - Karsten Nalbach
AU - Joana Petushi
AU - Pia Grundschöttel
AU - Jessica Wagner
AU - Valentine Thomas
AU - Janne Lamberty
AU - Emily Withers
AU - Hanna Huber
AU - Sabrina Hübschmann
AU - Ekaterina Semenova
AU - Paul Turko
AU - Andrew G. Newman
AU - Lisa Diez
AU - Marc Beyer
AU - Elena De Domenico
AU - Péter Körtvelyessy
AU - Dirk Reinhold
AU - Anja Schneider
AU - Jonas J. Neher
AU - T Ulas
AU - Stefan F. Lichtenthaler
AU - Benjamin R. Rost
AU - Dietmar Schmitz
AU - Harald Prüß
AU - Susanne Wegmann
PY - 2026
DA - 2026/05/13
JO - Science Advances
DO - 10.1126/sciadv.aec2042
UR - https://doi.org/10.1126/sciadv.aec2042
AB - 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.
SN - 2375-2548
ER -