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IgLON5 autoimmune antibodies activate Tau via neuronal hyperactivity.

Science advances

Authors: 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

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.

PMID: 42127169

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