Journal Article

DZNE-2026-00527

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png IgLON5 autoimmune antibodies activate Tau via neuronal hyperactivity.

Askin, B. (First author)DZNE* ; Kilic, C.DZNE* ; Cordero Gómez, C.DZNE* ; Duong, S. L.DZNE* ; Domingues-Baquero, A.DZNE* ; Goihl, A. ; Nalbach, K.DZNE* ; Petushi, J.DZNE* ; Grundschöttel, P.DZNE* ; Wagner, J.DZNE* ; Thomas, V.DZNE* ; Lamberty, J.DZNE* ; Withers, E.DZNE* ; Huber, H.DZNE* ; Hübschmann, S.DZNE* ; Semenova, E.DZNE* ; Turko, P. ; Newman, A. G. ; Diez, L.DZNE* ; Beyer, M.DZNE* ; De Domenico, E.DZNE* ; Körtvelyessy, P.DZNE* ; Reinhold, D. ; Schneider, A.DZNE* ; Neher, J. J.DZNE* ; Ulas, T.DZNE* ; Lichtenthaler, S. F.DZNE* ; Rost, B. R.DZNE* ; Schmitz, D.DZNE* ; Prüss, H.DZNE* ; Wegmann, S. (Last author)DZNE*

2026
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: doi:10.1126/sciadv.aec2042

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.

Keyword(s): tau Proteins: metabolism (MeSH) ; tau Proteins: immunology (MeSH) ; Animals (MeSH) ; Autoantibodies: immunology (MeSH) ; Humans (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: immunology (MeSH) ; Neurons: pathology (MeSH) ; Mice (MeSH) ; Cell Adhesion Molecules, Neuronal: immunology (MeSH) ; Cell Adhesion Molecules, Neuronal: metabolism (MeSH) ; Phosphorylation (MeSH) ; Hippocampus: metabolism (MeSH) ; Hippocampus: pathology (MeSH) ; Autoimmune Diseases: immunology (MeSH) ; Autoimmune Diseases: pathology (MeSH) ; Autoimmune Diseases: metabolism (MeSH) ; Male (MeSH) ; tau Proteins ; Autoantibodies ; Cell Adhesion Molecules, Neuronal ; IgLON5 protein, human

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Contributing Institute(s):

1. Protein Actions in Neurodegeneration (AG Wegmann)
2. Autoimmune Encephalopathies (AG Prüß)
3. Neuroproteomics (AG Lichtenthaler)
4. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
5. Neuroimmunology and Neurodegenerative Disease (AG Neher (München))
6. Translational Dementia Research (Bonn) (AG Schneider)
7. Immunogenomics and Neurodegeneration (AG Beyer)
8. Clinical Neurophysiology and Memory (AG Düzel)
9. Network Dysfunction (AG Schmitz)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
3. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
4. 351 - Brain Function (POF4-351) (POF4-351)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2026

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