Basic Science and Pathogenesis.

Background: Increasing evidence suggests that alternative splicing plays an important role in Alzheimer's disease (AD), a devastating neurodegenerative disorder involving the intracellular aggregation of hyperphosphorylated tau.

Method: We used whole transcriptome and targeted long-read cDNA sequencing to profile transcript diversity in the entorhinal cortex of wild-type (WT) and transgenic (TG) mice harbouring a mutant form of human tau.

Result: Whole transcriptome profiling showed that previously reported gene-level expression differences between WT and TG mice reflect changes in the abundance of specific transcripts. Ultradeep targeted long-read cDNA sequencing of genes implicated in AD revealed hundreds of novel isoforms and identified specific transcripts associated with the development of tau pathology.

Conclusion: 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 neuropathology. Our transcript annotations and a novel informatics pipeline for the analysis of long-read transcript sequencing data are provided as a resource to the community.