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

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 harbori...

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Bibliographic Details
Published in:Nature communications 2024-08, Vol.15 (1), p.6458-19, Article 6458
Main Authors: Leung, Szi Kay, Bamford, Rosemary A., Jeffries, Aaron R., Castanho, Isabel, Chioza, Barry, Flaxman, Christine S., Moore, Karen, Dempster, Emma L., Harvey, Joshua, Brown, Jonathan T., Ahmed, Zeshan, O’Neill, Paul, Richardson, Sarah J., Hannon, Eilis, Mill, Jonathan
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Language:English
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Summary: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. The authors used long-read sequencing to reveal novel isoforms and differential transcript use in a transgenic model of tau pathology. Similar patterns were found in the human cortex, supporting a role for alternative splicing in Alzheimer’s disease.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-50486-8