TYK2 mediates neuroinflammation in Alzheimer's disease brains with TDP-43 pathology

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.