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Long-read transcript sequencing identifies differential isoform expression in the entorhinal cortex in a transgenic model of tau pathology

Author

Listed:
  • Szi Kay Leung

    (University of Exeter)

  • Rosemary A. Bamford

    (University of Exeter)

  • Aaron R. Jeffries

    (University of Exeter)

  • Isabel Castanho

    (University of Exeter
    Beth Israel Deaconess Medical Center
    Harvard Medical School)

  • Barry Chioza

    (University of Exeter)

  • Christine S. Flaxman

    (University of Exeter)

  • Karen Moore

    (University of Exeter)

  • Emma L. Dempster

    (University of Exeter)

  • Joshua Harvey

    (University of Exeter)

  • Jonathan T. Brown

    (University of Exeter)

  • Zeshan Ahmed

    (Eli Lilly)

  • Paul O’Neill

    (University of Exeter)

  • Sarah J. Richardson

    (University of Exeter)

  • Eilis Hannon

    (University of Exeter)

  • Jonathan Mill

    (University of Exeter)

Abstract

Increasing evidence suggests that alternative splicing plays an important role in Alzheimer’s disease (AD) pathology. We used long-read sequencing in combination with a novel bioinformatics tool (FICLE) to profile transcript diversity in the entorhinal cortex of female transgenic (TG) mice harboring a mutant form of human tau. Our analyses revealed hundreds of novel isoforms and identified differentially expressed transcripts – including specific isoforms of Apoe, App, Cd33, Clu, Fyn and Trem2 – associated with the development of tau pathology in TG mice. Subsequent profiling of the human cortex from AD individuals and controls revealed similar patterns of transcript diversity, including the upregulation of the dominant TREM2 isoform in AD paralleling the increased expression of the homologous transcript in TG mice. Our results highlight the importance of differential transcript usage, even in the absence of gene-level expression alterations, as a mechanism underpinning gene regulation in the development of AD neuropathology.

Suggested Citation

  • Szi Kay Leung & Rosemary A. Bamford & Aaron R. Jeffries & Isabel Castanho & Barry Chioza & Christine S. Flaxman & Karen Moore & Emma L. Dempster & Joshua Harvey & Jonathan T. Brown & Zeshan Ahmed & Pa, 2024. "Long-read transcript sequencing identifies differential isoform expression in the entorhinal cortex in a transgenic model of tau pathology," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50486-8
    DOI: 10.1038/s41467-024-50486-8
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    References listed on IDEAS

    as
    1. Noam D. Beckmann & Wei-Jye Lin & Minghui Wang & Ariella T. Cohain & Alexander W. Charney & Pei Wang & Weiping Ma & Ying-Chih Wang & Cheng Jiang & Mickael Audrain & Phillip H. Comella & Amanda K. Fakir, 2020. "Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    2. Julia Gamache & Kellie Benzow & Colleen Forster & Lisa Kemper & Chris Hlynialuk & Eva Furrow & Karen H. Ashe & Michael D. Koob, 2019. "Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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