Evidence map›Paper›PMID 41832177›Full record

ArticleNature communications2026

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 and 15 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

25 authors.

Laura E König *Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.ORCID http://orcid.org/0000-0001-8154-4226
Steve Rodriguez *Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.
Clemens HugLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.ORCID http://orcid.org/0000-0002-8299-3274
Shayda DaneshvariLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.
Alexander ChungLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.ORCID http://orcid.org/0009-0008-4820-5570
Mark ApplemanLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.ORCID http://orcid.org/0009-0000-7380-8113
Max TsaiLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.
Gary A BradshawLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.
Asli SahinDepartment of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Charlestown, MA, USA.
Yuyu SongLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.ORCID http://orcid.org/0000-0002-9196-1610
George ZhouDepartment of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Charlestown, MA, USA.ORCID http://orcid.org/0000-0002-1345-2634
Robyn J EisertLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.ORCID http://orcid.org/0000-0001-7977-249X
Federica PiccioniBroad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-1210-3210
Christine MarquesDepartment of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Charlestown, MA, USA.
Sharon PowleyDepartment of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Charlestown, MA, USA.ORCID http://orcid.org/0009-0001-5614-0892
James YarmolinskyDementia Research Institute, Imperial College London, London, UK.
Brian J WaingerDepartment of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Charlestown, MA, USA.ORCID http://orcid.org/0000-0002-3664-7231
Sudeshna DasDepartment of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Charlestown, MA, USA.ORCID http://orcid.org/0000-0002-9486-6811
Marian KalocsayLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.ORCID http://orcid.org/0000-0002-4187-5829
Abbas DehghanDementia Research Institute, Imperial College London, London, UK.ORCID http://orcid.org/0000-0001-6403-016X
Ioanna TzoulakiDementia Research Institute, Imperial College London, London, UK.ORCID http://orcid.org/0000-0002-4275-9328
Artem SokolovLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.ORCID http://orcid.org/0000-0002-8056-0504
Peter SorgerLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.ORCID http://orcid.org/0000-0002-3364-1838
David E RootBroad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-5122-861X
Mark W AlbersLaboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA. albers.mark@mgh.harvard.edu.ORCID http://orcid.org/0000-0001-7855-3455

Funding

Harnessing Diverse Bioinformatic Approaches To Repurpose Drugs For Alzheimers Disease And Related DementiasR01AG058063 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI MARK W ALBERS, PETER Karl SORGER · 2018 to 2026
$7.8M
Defining the pathogenic relationship of TDP-43 inclusions and cytoplasmic double stranded RNA in AD and FTDR01AG078377 · NIA · HARVARD MEDICAL SCHOOL · PI MARK W ALBERS · 2025 to 2026
$1.6M
NIA NIH HHS R01 AG058063NIA NIH HHS R01 AG078377U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01 AG078297
6 · The paper itself

Abstract

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.

Indexed as

Alzheimer DiseaseBrainDNA-Binding ProteinsNeuroinflammatory DiseasesTYK2 KinaseAnimalsFemaleHumansMaleNeuronsPyrazolesPyrimidinesDNA-Binding ProteinsPyrazolesPyrimidinesTARDBP protein, humanTYK2 KinaseTYK2 protein, human

Identifiers

PMID41832177
PMCPMC13133158

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.