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A role for SC35 and hnRNPA1 in the determination of amyloid precursor protein isoforms

Molecular Psychiatry volume 12, pages 681–690 (2007)Cite this article

Abstract

The β-amyloid peptide (Aβ) that accumulates in senile plaques in Alzheimer's disease is formed by cleavage of the amyloid precursor protein (APP). The APP gene has several intronic Alu elements inserted in either the sense or antisense orientation. In this study, we demonstrate that binding of SC35 and hnRNPA1 to Alu elements on either side of exon 7 in the transcribed pre-mRNA is involved in alternative splicing of APP exons 7 and 8. Neuronal cells transfected with the full-length form of APP secrete higher levels of Aβ than cells transfected with the APP695 isoform lacking exons 7 and 8. Finally, we show that treatment of neuronal cells with estradiol results in increased expression of APP695, SC35 and hnRNPA1, and lowers the level of secreted Aβ. An understanding of the regulation of splicing of APP may lead to the identification of new targets for treating Alzheimer's disease.

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Acknowledgements

We are grateful to Dr A Fujiyama, RIKEN-GSC, Japan for providing clone S491 used in amplification of the APP minigenes, Dr R Killick, Institute of Psychiatry, Denmark Hill, London and Dr Sara Nakielny, Cancer Research UK London Research Institute for helpful discussions. This work was partly supported by Cancer Research UK.

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Authors and Affiliations

  1. Human Cytogenetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London, UK

    R Donev, A Newall & D Sheer

  2. Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, UK

    R Donev

  3. Molecular Psychiatry and Psychopharmacology, School of Medicine, University of Wales Swansea, Swansea, UK

    J Thome

  4. Neuroscience Centre, Institute of Cell and Molecular Science, Barts and the London, Queen Mary's School of Medicine and Dentistry, London, UK

    D Sheer

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Correspondence to R Donev or D Sheer.

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Donev, R., Newall, A., Thome, J. et al. A role for SC35 and hnRNPA1 in the determination of amyloid precursor protein isoforms. Mol Psychiatry 12, 681–690 (2007). https://doi.org/10.1038/sj.mp.4001971

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