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

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, Paul O’Neill, Sarah J. Richardson, Eilis Hannon and Jonathan Mill ()
Additional contact information
Szi Kay Leung: University of Exeter
Rosemary A. Bamford: University of Exeter
Aaron R. Jeffries: University of Exeter
Isabel Castanho: University of Exeter
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

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50486-8

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