TYK2 mediates neuroinflammation in Alzheimer’s disease brains with TDP-43 pathology
- Laura E. König
- Steve Rodriguez
- Clemens Hug
- Shayda Daneshvari
- Alexander Chung
- Mark Appleman
- Max Tsai
- Gary A. Bradshaw
- Asli Sahin
- Yuyu Song
- George Zhou
- Robyn J. Eisert
- Federica Piccioni
- Christine Marques
- Sharon Powley
- James Yarmolinsky
- Brian J. Wainger
- Sudeshna Das
- Marian Kalocsay
- Abbas Dehghan
- Ioanna Tzoulaki
- Artem Sokolov
- Peter Sorger
- David E. Root
- Mark W. Albers
2026-03-14
Neuroinflammation is a pathological feature of neurodegenerative diseases like Alzheimer’s disease and ALS. Cytoplasmic dsRNA (cdsRNA) triggers a type-I interferon response in human neural cells, leading to their death, and is found in neurons of C9ORF72 -ALS patients. Here, we report the spatial coincidence of cdsRNA and pTDP-43 inclusions in human postmortem tissue with Alzheimer’s disease pathology, and upregulated interferon response genes in affected regions. CdsRNA also accumulates in a human TDP-43 G298S iPSC cortical neuronal model. We use cryptic exon detection as a proxy for TDP-43 mislocalization and demonstrate that FDA-approved JAK inhibitors baricitinib and ruxolitinib, which block interferon signaling, show protective effects only in brains with elevated cryptic exon expression. A CRISPR screen reveals TYK2 as a top hit, and TYK2 knockdown and the selective TYK2 inhibitor deucravacitinib rescue cdsRNA-induced toxicity. We find parallel neuroinflammatory mechanisms, dependent on TYK2 - a potential disease-modifying target - for TDP-43-associated Alzheimer’s disease and C9ORF72 -ALS.