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TDP-43 pathology in familial British dementia

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Abstract

Trans-activation-responsive DNA-binding protein 43 (TDP-43) is a component of pathological inclusions in amyotrophic lateral sclerosis and several forms of sporadic and familial frontotemporal lobar degeneration. This has suggested defining a new class of diseases known as TDP-43 proteinopathies. However, it has been reported more recently that TDP-43 positive inclusions occur in other neurodegenerative disorders such as Alzheimer’s disease, Dementia with Lewy Bodies and Parkinsonism dementia complex of Guam. Here we report the occurrence of TDP-43 inclusions in one other neurodegenerative disorder: familial British dementia. Using a variety of antibodies against phosphorylated and non-phosphorylated TDP-43 epitopes, we found intense accumulation occurred in the form of dystrophic neurites, neuronal cytoplasmic inclusions and was also occasionally associated with neurofibrillary tangles. Double immunostaining revealed that TDP-43 and tau aggregates were rarely directly colocalized, but co-existed in the same neurons as separate inclusions. Double staining with ubiquitin showed a direct colocalization with TDP-43. The phosphorylation-dependent TDP-43 antibodies proved superior to phosphorylation-independent antibodies in revealing pathological inclusions since the former did not stain non-phosphorylated TDP-43 in normal nuclei. Our results support the concept that TDP-43 pathology is not narrowly restricted, but is involved in the etiology of many neurodegenerative disorders.

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Acknowledgments

We greatly appreciate the expert support with confocal imaging of Dr. Henry G. S. Martin (Vancouver, Canada). This research was supported by the Pacific Alzheimer Research Foundation.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Psychiatry, Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    Claudia Schwab, Sheng Yu & Patrick L. McGeer

  2. Department of Psychogeriatrics, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo, 156-8585, Japan

    Tetsuaki Arai & Haruhiko Akiyama

  3. Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo, 156-8585, Japan

    Masato Hasegawa

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  1. Claudia Schwab
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  2. Tetsuaki Arai
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  3. Masato Hasegawa
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  4. Haruhiko Akiyama
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  5. Sheng Yu
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  6. Patrick L. McGeer
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Correspondence to Patrick L. McGeer.

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Schwab, C., Arai, T., Hasegawa, M. et al. TDP-43 pathology in familial British dementia. Acta Neuropathol 118, 303–311 (2009). https://doi.org/10.1007/s00401-009-0514-3

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  • DOI: https://doi.org/10.1007/s00401-009-0514-3

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