TYK2 as a novel therapeutic target in Alzheimer's Disease with TDP-43 inclusions

Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD)^1,2 and amyotrophic lateral sclerosis (ALS)³, raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS⁴. CdsRNA triggers a type-I interferon (IFN-I)-based innate immune response in human neural cells, resulting in their death⁴. Here, we report that cdsRNA is also spatially coincident with pTDP-43 cytoplasmic inclusions in brain cells of patients with AD pathology and that type-I interferon response genes are significantly upregulated in brain regions affected by AD. We updated our machine-learning pipeline DRIAD-SP (Drug Repurposing In Alzheimer's Disease with Systems Pharmacology) to incorporate cryptic exon (CE) detection as a proxy of pTDP-43 inclusions and demonstrated that the FDA-approved JAK inhibitors baricitinib and ruxolitinib that block interferon signaling show a protective signal only in cortical brain regions expressing multiple CEs. Furthermore, the JAK family member Tyk2 was a top hit in a CRISPR screen of cdsRNA-mediated death in differentiated human neural cells. The selective Tyk2 Inhibitor deucravacitinib, an FDA-approved drug for psoriasis, rescued toxicity elicited by cdsRNA. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive biomarkers for cdsRNA-related neurodegenerative diseases. Together, we find parallel neuroinflammatory mechanisms between TDP-43 associated-AD and ALS and nominate Tyk2 as a possible disease-modifying target of these incurable neurodegenerative diseases.