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JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer’s disease

Author

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  • Chiara Scopa

    (Thomas Jefferson University
    Thomas Jefferson University)

  • Samantha M. Barnada

    (Thomas Jefferson University)

  • Maria E. Cicardi

    (Thomas Jefferson University)

  • Mo Singer

    (Thomas Jefferson University)

  • Davide Trotti

    (Thomas Jefferson University)

  • Marco Trizzino

    (Thomas Jefferson University
    Imperial College London)

Abstract

Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer’s disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.

Suggested Citation

  • Chiara Scopa & Samantha M. Barnada & Maria E. Cicardi & Mo Singer & Davide Trotti & Marco Trizzino, 2023. "JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43728-8
    DOI: 10.1038/s41467-023-43728-8
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    1. Simone M. Haag & Muhammet F. Gulen & Luc Reymond & Antoine Gibelin & Laurence Abrami & Alexiane Decout & Michael Heymann & F. Gisou van der Goot & Gerardo Turcatti & Rayk Behrendt & Andrea Ablasser, 2018. "Targeting STING with covalent small-molecule inhibitors," Nature, Nature, vol. 559(7713), pages 269-273, July.
    2. Dieter-Chichung Lie & Sophia A. Colamarino & Hong-Jun Song & Laurent Désiré & Helena Mira & Antonella Consiglio & Edward S. Lein & Sebastian Jessberger & Heather Lansford & Alejandro R. Dearie & Fred , 2005. "Wnt signalling regulates adult hippocampal neurogenesis," Nature, Nature, vol. 437(7063), pages 1370-1375, October.
    3. Mason A. Israel & Shauna H. Yuan & Cedric Bardy & Sol M. Reyna & Yangling Mu & Cheryl Herrera & Michael P. Hefferan & Sebastiaan Van Gorp & Kristopher L. Nazor & Francesca S. Boscolo & Christian T. Ca, 2012. "Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells," Nature, Nature, vol. 482(7384), pages 216-220, February.
    4. Muhammet F. Gulen & Ute Koch & Simone M. Haag & Fabian Schuler & Lionel Apetoh & Andreas Villunger & Freddy Radtke & Andrea Ablasser, 2017. "Signalling strength determines proapoptotic functions of STING," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
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