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Beta-Amyloid Increases the Expression Levels of Tid1 Responsible for Neuronal Cell Death and Amyloid Beta Production

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Abstract

Mitochondrial dysfunctions and oxidative stress play important roles in the early pathogenesis of Alzheimer’s disease (AD), which also involves the aberrant expression levels of mitochondrial proteins. However, the molecular mechanisms underlying the aberrant expression levels of these proteins in the pathogenesis of AD are still not completely understood. Tid1 (DnaJA3/mtHsp40), a mammalian homolog of the Drosophila tumor suppressor Tid56, is reported to induce mitochondrial fragmentation associated with an increase in reactive oxygen species (ROS) levels, resulting in cell death in some cancer cells. However, the involvement of Tid1 in AD pathogenesis is as yet unknown. In this study, we found that the Tid1 protein levels were upregulated in the hippocampus of AD patients and Tg2576 mice. Our in vitro studies showed that Aβ42 increased the expression levels of Tid1 in primary rat cortical neurons. The knockdown of Tid1 protected against neuronal cell death induced by Aβ42, and Tid1-mediated neuronal cell death, was dependent on the increased ROS generation and caspase-3 activity. The overexpression of Tid1 in HEK293-APP cells increased the BACE1 levels, resulting in increased Aβ production. Conversely, Tid1 knockdown in HEK293-APP cells and primary cultured neurons decreased Aβ production through the reduction in the BACE1 levels. We also found that the overexpression of Tid1 activated c-Jun N-terminal kinase (JNK) leading to increased Aβ production. Taken together, our results suggest that upregulated Tid1 levels in the hippocampus of patients with AD and Tg2576 mice induce apoptosis and increase Aβ production, and Tid1 may therefore be a suitable target in therapeutic interventions for AD.

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Funding

This work was supported by a Grant-in-Aid for Scientific Research B (16H05559) and a Grant-in-Aid for challenging Exploratory Research (15K15712) (to M.M.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. This work was also supported by the Project of translational and clinical research seed A from Japan Agency for Medical Research and Development (AMED, A-128) (to M.M).

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Authors and Affiliations

  1. Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan

    Chunyu Zhou, Ferdous Taslima, Mona Abdelhamid, Makoto Michikawa & Cha-Gyun Jung

  2. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada

    Sung-Woo Kim

  3. Department of Community-based Medical Education, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Hiroyasu Akatsu

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  1. Chunyu Zhou
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Contributions

C.Y.Z., F.T., M.A., and C.G.J. performed the experiments. C.Y.Z., C.G.J., and M.M designed all the experiments, analyzed the data, and wrote the paper. S.W.K. and H.A. contributed to the discussion of the experiments. All authors read and approved the final manuscript.

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Correspondence to Makoto Michikawa or Cha-Gyun Jung.

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All animal experiments were performed in accordance with institutional guidelines and approved by the Nagoya City University and all participants signed informed consent.

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Supplementary Fig. 1

Tid1 does not affect Aβ level in HEK293-C99 cells. (A and B) HEK293-C99 cells were transfected with the mock control (Myc) or Myc-tagged Tid1-L (Myc-Tid1-L) vector for 48 h. (C and D) HEK293-C99 cells were transfected with the control or Tid1 siRNA for 72 h. The levels of Aβ40 and Aβ42 secreted in the medium were measured by sandwich ELISA. The Aβ levels were normalized to the amount of total protein in the cells. All the values are presented as the mean ± SEM of three independent experiments. N.S., no significant difference, as determined by Student’s t-test. (PNG 776 kb)

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Zhou, C., Taslima, F., Abdelhamid, M. et al. Beta-Amyloid Increases the Expression Levels of Tid1 Responsible for Neuronal Cell Death and Amyloid Beta Production. Mol Neurobiol 57, 1099–1114 (2020). https://doi.org/10.1007/s12035-019-01807-2

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