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<p>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 <i>C9ORF72</i>-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 <i>TYK2</i> as a top hit, and <i>TYK2</i> 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 <i>C9ORF72</i>-ALS.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月14日

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  • 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

摘要

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.