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No alteration in tau exon 10 alternative splicing in tangle-bearing neurons of the Alzheimer’s disease brain

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Abstract

Defective splicing of tau mRNA, promoting a shift between tau isoforms with (4R tau) and without (3R tau) exon 10, is believed to be a pathological consequence of certain tau mutations causing frontotemporal dementia. By assessing protein and mRNA levels of 4R tau and 3R tau in 27 AD and 20 control temporal cortex, we investigated whether altered tau splicing is a feature also in Alzheimer’s disease (AD). However, apart from an expected increase of sarcosyl-insoluble tau in AD, there were no significant differences between the groups. Next, by laser-capture microscopy and quantitative PCR, we separately analyzed CA1 hippocampal neurons with and without neurofibrillary pathology from six of the AD and seven of the control brains. No statistically significant differences in 4R tau/3R tau mRNA were found between the different subgroups. Moreover, we confirmed the absence of significant ratio differences in a second data set with laser-captured entorhinal cortex neurons from four AD and four control brains. Finally, the 4R tau/3R tau ratio in CA1 neurons was roughly half of the ratio in temporal cortex, indicating region-specific differences in tau mRNA splicing. In conclusion, this study indicated region-specific and possibly cell-type-specific tau splicing but did not lend any support to overt changes in alternative splicing of tau exon 10 being an underlying factor in AD pathogenesis.

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Acknowledgments

This study was supported by NIH (P50 AG005134 and AG08487) and the Rubenstein Foundation. M.I. was sponsored by The Swedish Society of Medicine, The Swedish Alzheimer Foundation and the Swedish Research Council. RdeS was funded by the Reta Lila Weston Trust for Medical Research. We are also grateful to Karlotta Fitch for technical support.

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Authors and Affiliations

  1. Harvard Medical School, Massachusetts General Hospital, 114 16th Street, Charlestown, MA, 02129, USA

    Martin Ingelsson, Karunya Ramasamy, Ippolita Cantuti-Castelvetri, Toshifumi Matsui, Jennifer Orne, Hasimoto Kowa, Susan Raju, Charles R. Vanderburg, Jean C. Augustinack, John H. Growdon, Matthew P. Frosch, David G. Standaert, Michael C. Irizarry & Bradley T. Hyman

  2. Department of Public Health/Molecular Geriatrics, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden

    Martin Ingelsson, Lena Skoglund & Lars Lannfelt

  3. Reta Lila Weston Institute of Neurological Studies, University College London, 1 Wakefield Street, London, WC1N 1PG, UK

    Rohan de Silva & Andrew J. Lees

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  1. Martin Ingelsson
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  2. Karunya Ramasamy
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  14. John H. Growdon
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  15. Matthew P. Frosch
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  18. Bradley T. Hyman
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Correspondence to Martin Ingelsson.

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Ingelsson, M., Ramasamy, K., Cantuti-Castelvetri, I. et al. No alteration in tau exon 10 alternative splicing in tangle-bearing neurons of the Alzheimer’s disease brain. Acta Neuropathol 112, 439–449 (2006). https://doi.org/10.1007/s00401-006-0095-3

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  • DOI: https://doi.org/10.1007/s00401-006-0095-3

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