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

  • Chunyu Zhou
  • Ferdous Taslima
  • Mona Abdelhamid
  • Sung-Woo Kim
  • Hiroyasu Akatsu
  • Makoto MichikawaEmail author
  • Cha-Gyun JungEmail author


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.


Alzheimer’s disease Tid1 Mitochondrial protein Neuronal cell death ROS β-Amyloid BACE1 JNK 


Authors’ 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.

Funding information

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.

Supplementary material

12035_2019_1807_Fig9_ESM.png (776 kb)
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)

12035_2019_1807_MOESM1_ESM.tiff (2.9 mb)
High Resolution Image (TIFF 2927 kb)


  1. 1.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356. CrossRefPubMedGoogle Scholar
  2. 2.
    Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698–712. CrossRefPubMedGoogle Scholar
  3. 3.
    Buxbaum JD, Liu KN, Luo Y, Slack JL, Stocking KL, Peschon JJ, Johnson RS, Castner BJ et al (1998) Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem 273(43):27765–27767. CrossRefPubMedGoogle Scholar
  4. 4.
    Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE et al (1999) Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 14(6):419–427. CrossRefPubMedGoogle Scholar
  5. 5.
    Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F (1999) Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci U S A 96(7):3922–3927. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J (2000) Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A 97(4):1456–1460. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Benard G, Bellance N, James D, Parrone P, Fernandez H, Letellier T, Rossignol R (2007) Mitochondrial bioenergetics and structural network organization. J Cell Sci 120(Pt 5):838–848. CrossRefPubMedGoogle Scholar
  8. 8.
    Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D et al (2005) Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J 19(14):2040–2041. CrossRefPubMedGoogle Scholar
  9. 9.
    Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15(9):1437–1449. CrossRefPubMedGoogle Scholar
  10. 10.
    Sorrentino V, Romani M, Mouchiroud L, Beck JS, Zhang H, D’Amico D, Moullan N, Potenza F et al (2017) Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity. Nature 552(7684):187–193. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Moehle EA, Shen K, Dillin A (2019) Mitochondrial proteostasis in the context of cellular and organismal health and aging. J Biol Chem 294(14):5396–5407. CrossRefPubMedGoogle Scholar
  12. 12.
    Baker MJ, Tatsuta T, Langer T (2011) Quality control of mitochondrial proteostasis. Cold Spring Harb Perspect Biol 3(7). CrossRefGoogle Scholar
  13. 13.
    Moreira PI, Cardoso SM, Santos MS, Oliveira CR (2006) The key role of mitochondria in Alzheimer’s disease. J Alzheimers Dis 9(2):101–110CrossRefGoogle Scholar
  14. 14.
    Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G (2010) Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochim Biophys Acta 1802(1):2–10. CrossRefPubMedGoogle Scholar
  15. 15.
    Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta 1842(8):1240–1247. CrossRefPubMedGoogle Scholar
  16. 16.
    Onyango IG, Dennis J, Khan SM (2016) Mitochondrial dysfunction in Alzheimer’s disease and the rationale for bioenergetics based therapies. Aging Dis 7(2):201–214. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795. CrossRefPubMedGoogle Scholar
  18. 18.
    Reddy PH, McWeeney S, Park BS, Manczak M, Gutala RV, Partovi D, Jung Y, Yau V et al (2004) Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer’s disease. Hum Mol Genet 13(12):1225–1240. CrossRefPubMedGoogle Scholar
  19. 19.
    Syken J, De-Medina T, Munger K (1999) TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions. Proc Natl Acad Sci U S A 96(15):8499–8504. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ng AC, Baird SD, Screaton RA (2014) Essential role of TID1 in maintaining mitochondrial membrane potential homogeneity and mitochondrial DNA integrity. Mol Cell Biol 34(8):1427–1437. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ahn BY, Trinh DL, Zajchowski LD, Lee B, Elwi AN, Kim SW (2010) Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer. Oncogene 29(8):1155–1166. CrossRefPubMedGoogle Scholar
  22. 22.
    Elwi AN, Lee B, Meijndert HC, Braun JE, Kim SW (2012) Mitochondrial chaperone DnaJA3 induces Drp1-dependent mitochondrial fragmentation. Int J Biochem Cell Biol 44(8):1366–1376. CrossRefPubMedGoogle Scholar
  23. 23.
    Jung CG, Uhm KO, Horike H, Kim MJ, Misumi S, Ishida A, Ueda Y, Choi EK et al (2015) Auraptene increases the production of amyloid-beta via c-Jun N-terminal kinase-dependent activation of gamma-secretase. J Alzheimers Dis 43(4):1215–1228. CrossRefPubMedGoogle Scholar
  24. 24.
    Hatakeyama S, Matsumoto M, Kamura T, Murayama M, Chui DH, Planel E, Takahashi R, Nakayama KI et al (2004) U-box protein carboxyl terminus of Hsc70-interacting protein (CHIP) mediates poly-ubiquitylation preferentially on four-repeat Tau and is involved in neurodegeneration of tauopathy. J Neurochem 91(2):299–307. CrossRefPubMedGoogle Scholar
  25. 25.
    Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG (2001) Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci 21(2):372–381CrossRefGoogle Scholar
  26. 26.
    Hoekstra JG, Hipp MJ, Montine TJ, Kennedy SR (2016) Mitochondrial DNA mutations increase in early stage Alzheimer disease and are inconsistent with oxidative damage. Ann Neurol 80(2):301–306. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Pagani L, Eckert A (2011) Amyloid-Beta interaction with mitochondria. Int J Alzheimers Dis 2011:925050. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Chen CY, Chiou SH, Huang CY, Jan CI, Lin SC, Hu WY, Chou SH, Liu CJ et al (2009) Tid1 functions as a tumour suppressor in head and neck squamous cell carcinoma. J Pathol 219(3):347–355. CrossRefPubMedGoogle Scholar
  29. 29.
    Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F (2018) Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol 14:450–464. CrossRefPubMedGoogle Scholar
  30. 30.
    Son Y, Cheong YK, Kim NH, Chung HT, Kang DG, Pae HO (2011) Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways? J Signal Transduct 2011:792639. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Santabarbara-Ruiz P, Lopez-Santillan M, Martinez-Rodriguez I, Binagui-Casas A, Perez L, Milan M, Corominas M, Serras F (2015) ROS-induced JNK and p38 signaling is required for unpaired cytokine activation during Drosophila regeneration. PLoS Genet 11(10):e1005595. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Oswald MCW, Garnham N, Sweeney ST, Landgraf M (2018) Regulation of neuronal development and function by ROS. FEBS Lett 592(5):679–691. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Shen C, Chen Y, Liu H, Zhang K, Zhang T, Lin A, Jing N (2008) Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma-secretase. J Biol Chem 283(25):17721–17730. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Haun F, Nakamura T, Lipton SA (2013) Dysfunctional mitochondrial dynamics in the pathophysiology of neurodegenerative diseases. J Cell Death 6:27–35. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Haun F, Nakamura T, Shiu AD, Cho DH, Tsunemi T, Holland EA, La Spada AR, Lipton SA (2013) S-nitrosylation of dynamin-related protein 1 mediates mutant huntingtin-induced mitochondrial fragmentation and neuronal injury in Huntington’s disease. Antioxid Redox Signal 19(11):1173–1184. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Mishra P, Chan DC (2014) Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol 15(10):634–646. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Aluise CD, Robinson RA, Beckett TL, Murphy MP, Cai J, Pierce WM, Markesbery WR, Butterfield DA (2010) Preclinical Alzheimer disease: brain oxidative stress, Abeta peptide and proteomics. Neurobiol Dis 39(2):221–228. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Pallas M, Camins A, Smith MA, Perry G, Lee HG, Casadesus G (2008) From aging to Alzheimer’s disease: unveiling “the switch” with the senescence-accelerated mouse model (SAMP8). J Alzheimers Dis 15(4):615–624CrossRefGoogle Scholar
  39. 39.
    Singh M, Dang TN, Arseneault M, Ramassamy C (2010) Role of by-products of lipid oxidation in Alzheimer’s disease brain: a focus on acrolein. J Alzheimers Dis 21(3):741–756. CrossRefPubMedGoogle Scholar
  40. 40.
    Aliev G (2011) Oxidative stress induced-metabolic imbalance, mitochondrial failure, and cellular hypoperfusion as primary pathogenetic factors for the development of Alzheimer disease which can be used as a alternate and successful drug treatment strategy: past, present and future. CNS Neurol Disord Drug Targets 10(2):147–148CrossRefGoogle Scholar
  41. 41.
    Butterfield DA, Boyd-Kimball D (2004) Amyloid beta-peptide(1-42) contributes to the oxidative stress and neurodegeneration found in Alzheimer disease brain. Brain Pathol 14(4):426–432CrossRefGoogle Scholar
  42. 42.
    Christen Y (2000) Oxidative stress and Alzheimer disease. Am J Clin Nutr 71(2):621S–629S. CrossRefPubMedGoogle Scholar
  43. 43.
    Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, Murphy MP, Szeto HH, Park B et al (2010) Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer’s disease neurons. J Alzheimers Dis 20(Suppl 2):S609–S631. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X (2008) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A 105(49):19318–19323. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Manczak M, Calkins MJ, Reddy PH (2011) Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer’s disease: implications for neuronal damage. Hum Mol Genet 20(13):2495–2509. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Edwards KM, Munger K (2004) Depletion of physiological levels of the human TID1 protein renders cancer cell lines resistant to apoptosis mediated by multiple exogenous stimuli. Oncogene 23(52):8419–8431. CrossRefPubMedGoogle Scholar
  47. 47.
    Kruman II, Wersto RP, Cardozo-Pelaez F, Smilenov L, Chan SL, Chrest FJ, Emokpae R Jr, Gorospe M et al (2004) Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron 41(4):549–561CrossRefGoogle Scholar
  48. 48.
    Uberti D, Ferrari Toninelli G, Memo M (2003) Involvement of DNA damage and repair systems in neurodegenerative process. Toxicol Lett 139(2-3):99–105CrossRefGoogle Scholar
  49. 49.
    Trinh DL, Elwi AN, Kim SW (2010) Direct interaction between p53 and Tid1 proteins affects p53 mitochondrial localization and apoptosis. Oncotarget 1(6):396–404. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Paola D, Domenicotti C, Nitti M, Vitali A, Borghi R, Cottalasso D, Zaccheo D, Odetti P et al (2000) Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells. Biochem Biophys Res Commun 268(2):642–646. CrossRefPubMedGoogle Scholar
  51. 51.
    Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A et al (2005) Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem 92(3):628–636. CrossRefPubMedGoogle Scholar
  52. 52.
    Tong Y, Zhou W, Fung V, Christensen MA, Qing H, Sun X, Song W (2005) Oxidative stress potentiates BACE1 gene expression and Abeta generation. J Neural Transm (Vienna) 112(3):455–469. CrossRefGoogle Scholar
  53. 53.
    Fukumoto H, Cheung BS, Hyman BT, Irizarry MC (2002) Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59(9):1381–1389CrossRefGoogle Scholar
  54. 54.
    Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G (2002) Increased expression of the amyloid precursor beta-secretase in Alzheimer’s disease. Ann Neurol 51(6):783–786. CrossRefPubMedGoogle Scholar
  55. 55.
    Matsui T, Ingelsson M, Fukumoto H, Ramasamy K, Kowa H, Frosch MP, Irizarry MC, Hyman BT (2007) Expression of APP pathway mRNAs and proteins in Alzheimer’s disease. Brain Res 1161:116–123. CrossRefPubMedGoogle Scholar
  56. 56.
    Yang LB, Lindholm K, Yan R, Citron M, Xia W, Yang XL, Beach T, Sue L et al (2003) Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 9(1):3–4. CrossRefPubMedGoogle Scholar
  57. 57.
    Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103(2):239–252CrossRefGoogle Scholar
  58. 58.
    Puig B, Gomez-Isla T, Ribe E, Cuadrado M, Torrejon-Escribano B, Dalfo E, Ferrer I (2004) Expression of stress-activated kinases c-Jun N-terminal kinase (SAPK/JNK-P) and p38 kinase (p38-P), and tau hyperphosphorylation in neurites surrounding betaA plaques in APP Tg2576 mice. Neuropathol Appl Neurobiol 30(5):491–502. CrossRefPubMedGoogle Scholar
  59. 59.
    Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, Boux H, Smith MA (2001) Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer’s disease. J Neurochem 76(2):435–441CrossRefGoogle Scholar
  60. 60.
    Niu G, Zhang H, Liu D, Chen L, Belani C, Wang HG, Cheng H (2015) Tid1, the mammalian homologue of Drosophila tumor suppressor Tid56, mediates macroautophagy by interacting with Beclin1-containing autophagy protein complex. J Biol Chem 290(29):18102–18110. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of BiochemistryNagoya City University Graduate School of Medical SciencesNagoyaJapan
  2. 2.Department of Biochemistry and Molecular BiologyUniversity of CalgaryCalgaryCanada
  3. 3.Department of Community-based Medical EducationNagoya City University Graduate School of Medical SciencesNagoyaJapan

Personalised recommendations