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Casein kinase-1 isoforms differentially associate with neurofibrillary and granulovacuolar degeneration lesions

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Abstract

Alzheimer’s Disease (AD) is characterized by the appearance of neurofibrillary and granulovacuolar lesions in the brains of affected individuals. The former is composed of hyperphosphorylated aggregates of the microtubule-associated protein tau. The latter is poorly characterized but reacts strongly with anti-phosphoepitope antibodies indicating that it too accumulates phosphoproteins. Both lesions react strongly with antibodies directed against members of the casein kinase-1 family of phosphotransferases, a group of closely related protein kinases that frequently function in tandem with the ubiquitin modification system. To determine whether individual members of the casein kinase-1 family differentially associate with AD lesions, hippocampal sections isolated from late stage cases of AD were subjected to double-label fluorescence immunohistochemistry using a panel of selective anti-casein kinase 1 antibodies and small-molecule fluorochromes thioflavin S and thiazin red. The resultant colocalization patterns revealed that the alpha CK1 isoform strongly correlated with thioflavin S and thiazin red fluorescence, indicating that it preferentially associated with neurofibrillary lesions. In contrast, the delta isoform staining pattern was dominated by colocalization with granulovacuolar degeneration bodies. These findings suggest that granulovacuolar and neurofibrillary lesions occupy separate populations of neurons, and implicate CK1 isoforms in the generation of lesion-associated phosphoepitopes. They also suggest a nexus between the phosphorylation and ubiquitination modifications found in both lesions.

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Acknowledgements

We thank Profs. L.I. Binder and R.W. Berry (Northwestern University, Il) for guidance with immunostaining, and to Prof. Paul D. Coleman and Dr. Linda M. Callahan (University of Rochester, NY) for generous access to tissue. We also thank Prof. Richard Burry, Ms. Kathy Wolken and Mr. Brian Kemmenoe (Campus Microscopic and Imaging facility, Ohio State University, OH) for guidance with confocal microscopy. This work was supported by NIH grants AG14452 (J.K.), AG16756 (D.D.V.), MH/NS31862 (Harvard Brain Tissue Resource Center), AG018254 (Rochester AD Core Center), and AG010161 (Rush AD Core Center).

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  1. Center for Molecular Neurobiology, Ohio State University College of Medicine , Columbus, OH, 43210, USA

    Theresa J. Kannanayakal & Jeff Kuret

  2. Department of Cell Biology and Physiology, Ohio State University College of Medicine , Columbus, OH, 43210, USA

    Haiyang Tao & Dale D. Vandre

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  1. Theresa J. Kannanayakal
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Kannanayakal, T.J., Tao, H., Vandre, D.D. et al. Casein kinase-1 isoforms differentially associate with neurofibrillary and granulovacuolar degeneration lesions. Acta Neuropathol 111, 413–421 (2006). https://doi.org/10.1007/s00401-006-0049-9

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  • DOI: https://doi.org/10.1007/s00401-006-0049-9

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