Beta-Amyloid Increases the Expression Levels of Tid1 Responsible for Neuronal Cell Death and Amyloid Beta Production
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.
KeywordsAlzheimer’s disease Tid1 Mitochondrial protein Neuronal cell death ROS β-Amyloid BACE1 JNK
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.
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).
Compliance and Ethical Standards
All animal experiments were performed in accordance with institutional guidelines and approved by the Nagoya City University and all participants signed informed consent.
Conflict of Interest
The authors declare that they have no conflict of interest.
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