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Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies

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Abstract

Phosphorylated and proteolytically cleaved TDP-43 is a major component of the ubiquitin-positive inclusions in the most common pathological subtype of frontotemporal lobar degeneration (FTLD-U). Intracellular accumulation of TDP-43 is observed in a subpopulation of patients with other dementia disorders, including Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). However, the pathological significance of TDP-43 pathology in these disorders is unknown, since biochemical features of the TDP-43 accumulated in AD and DLB brains, especially its phosphorylation sites and pattern of fragmentation, are still unclear. To address these issues, we performed immunohistochemical and biochemical analyses of AD and DLB cases, using phosphorylation-dependent anti-TDP-43 antibodies. We found a higher frequency of pathological TDP-43 in AD (36–56%) and in DLB (53–60%) than previously reported. Of the TDP-43-positive cases, about 20–30% showed neocortical TDP-43 pathology resembling the FTLD-U subtype associated with progranulin gene (PGRN) mutations. Immunoblot analyses of the sarkosyl-insoluble fraction from cases with neocortical TDP-43 pathology showed intense staining of several low-molecular-weight bands, corresponding to C-terminal fragments of TDP-43. Interestingly, the band pattern of these C-terminal fragments in AD and DLB also corresponds to that previously observed in the FTLD-U subtype associated with PGRN mutations. These results suggest that the morphological and biochemical features of TDP-43 pathology are common between AD or DLB and a specific subtype of FTLD-U. There may be genetic factors, such as mutations or genetic variants of PGRN underlying the co-occurrence of abnormal deposition of TDP-43, tau and α-synuclein.

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Acknowledgments

We thank Ms. H. Kondo, Ms. Y. Izumiyama, Ms. C. Haga and Ms. M. Luk for their excellent technical assistance. This research was supported by a Grant-in-Aid for Scientific Research (C) (to TA), a Grant-in-Aid for Scientific Research on Priority Areas—Research on Pathomechanisms of Brain Disorders (to MH), a Grant-in-Aid for Scientific Research (B) (to MH) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a grant from the Canadian Institutes of Health Research (grant # 74580) (to IM) and a grant from the Pacific Alzheimer Research Foundation (to IM).

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Authors and Affiliations

  1. 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

  2. Department of Pathology, Vancouver General Hospital, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada

    Ian R. A. Mackenzie

  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 & Takashi Nonoka

  4. Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1 Kamikitazawa, Setagaya-ku, Tokyo, 156-0057, Japan

    Kazhuhiro Niizato

  5. Department of Laboratory Medicine and Pathology, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1 Kamikitazawa, Setagaya-ku, Tokyo, 156-0057, Japan

    Kuniaki Tsuchiya

  6. Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan

    Shuji Iritani

  7. Department of Neuropsychiatry, National Shimofusa Mental Hospital, Chiba, 266-0007, Japan

    Mitsumoto Onaya

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  1. Tetsuaki Arai
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Correspondence to Tetsuaki Arai.

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Arai, T., Mackenzie, I.R.A., Hasegawa, M. et al. Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117, 125–136 (2009). https://doi.org/10.1007/s00401-008-0480-1

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