TYK2 mediates neuroinflammation in Alzheimer's disease brains with TDP-43 pathology - PubMed
3 hours ago
- #Alzheimer's disease
- #Neuroinflammation
- #TYK2
- Neuroinflammation is a key feature in neurodegenerative diseases like Alzheimer's disease and ALS.
- Cytoplasmic dsRNA (cdsRNA) triggers a type-I interferon response in human neural cells, leading to cell death, and is found in neurons of C9ORF72-ALS patients.
- Spatial coincidence of cdsRNA and pTDP-43 inclusions observed in Alzheimer's disease postmortem tissue, with upregulated interferon response genes in affected regions.
- CdsRNA accumulation also noted in a human TDP-43 G298S iPSC cortical neuronal model.
- FDA-approved JAK inhibitors baricitinib and ruxolitinib show protective effects only in brains with elevated cryptic exon expression, indicating TDP-43 mislocalization.
- CRISPR screen identifies TYK2 as a key mediator; its knockdown and the selective inhibitor deucravacitinib rescue cdsRNA-induced toxicity.
- TYK2 is highlighted as a potential disease-modifying target for TDP-43-associated Alzheimer's disease and C9ORF72-ALS.