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Caspase-Cleaved Tau Impairs Mitochondrial Dynamics in Alzheimer’s Disease

Molecular Neurobiology volume 55, pages 1004–1018 (2018)Cite this article

Abstract

Alzheimer’s disease (AD) is characterized by the presence of aggregates of tau protein. Tau truncated by caspase-3 (D421) or tau hyperphosphorylated at Ser396/S404 might play a role in the pathogenesis of AD. Mitochondria are dynamic organelles that modify their size and function through mitochondrial dynamics. Recent studies have shown that alterations of mitochondrial dynamics affect synaptic communication. Therefore, we studied the effects of pathological forms of tau on the regulation of mitochondrial dynamics. We used primary cortical neurons from tau(−/−) knockout mice and immortalized cortical neurons (CN1.4) that were transfected with plasmids containing green fluorescent protein (GFP) or GFP with different tau forms: full-length (GFP-T4), truncated (GFP-T4C3), pseudophosphorylated (GFP-T42EC), or both truncated and pseudophosphorylated modifications of tau (GFP-T4C3-2EC). Cells expressing truncated tau showed fragmented mitochondria compared to cells that expressed full-length tau. These findings were corroborated using primary neurons from tau(−/−) knockout mice that expressed the truncated and both truncated and pseudophosphorylated forms of tau. Interestingly, mitochondrial fragmentation was accompanied by a significant reduction in levels of optic atrophy protein 1 (Opa1) in cells expressing the truncated form of tau. In addition, treatment with low concentrations of amyloid-beta (Aβ) significantly reduced mitochondrial membrane potential, cell viability, and mitochondrial length in cortical cells and primary neurons from tau(−/−) mice that express truncated tau. These results indicate that the presence of tau pathology impairs mitochondrial dynamics by reducing Opa1 levels, an event that could lead to mitochondrial impairment observed in AD.

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References

  1. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362(4):329–344. doi:10.1056/NEJMra0909142

    CAS  Article  PubMed  Google Scholar 

  2. Rissman RA, Poon WW, Blurton-Jones M, Oddo S, Torp R, Vitek MP, LaFerla FM, Rohn TT et al (2004) Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 114(1):121–130. doi:10.1172/JCI20640

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Cho JH, Johnson GV (2004) Glycogen synthase kinase 3 beta induces caspase-cleaved tau aggregation in situ. J Biol Chem 279(52):54716–54723. doi:10.1074/jbc.M403364200

    CAS  Article  PubMed  Google Scholar 

  4. Lee S, Shea TB (2012) Caspase-mediated truncation of tau potentiates aggregation. Int J Alzheimers Dis 2012:731063. doi:10.1155/2012/731063

    PubMed  PubMed Central  Google Scholar 

  5. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P et al (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307(5713):1282–1288. doi:10.1126/science.1105681

    CAS  Article  PubMed  Google Scholar 

  6. Cowan CM, Bossing T, Page A, Shepherd D, Mudher A (2010) Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo. Acta Neuropathol 120(5):593–604. doi:10.1007/s00401-010-0716-8

    CAS  Article  PubMed  Google Scholar 

  7. Plouffe V, Mohamed NV, Rivest-McGraw J, Bertrand J, Lauzon M, Leclerc N (2012) Hyperphosphorylation and cleavage at D421 enhance tau secretion. PLoS One 7(5):e36873. doi:10.1371/journal.pone.0036873

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Zhang Y, Chen L, Shen G, Zhao Q, Shangguan L, He M (2014) GRK5 dysfunction accelerates tau hyperphosphorylation in APP (swe) mice through impaired cholinergic activity. Neuroreport 25(7):542–547. doi:10.1097/WNR.0000000000000142

    PubMed  Google Scholar 

  9. Dixit R, Ross JL, Goldman YE, Holzbaur EL (2008) Differential regulation of dynein and kinesin motor proteins by tau. Science 319(5866):1086–1089. doi:10.1126/science.1152993

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Dolan PJ, Johnson GV (2010) The role of tau kinases in Alzheimer’s disease. Curr Opin Drug Discov Dev 13(5):595–603

    CAS  Google Scholar 

  11. Quintanilla RA, Dolan PJ, Jin YN, Johnson GV (2012) Truncated tau and Abeta cooperatively impair mitochondria in primary neurons. Neurobiol Aging 33(3):e625–e635. doi:10.1016/j.neurobiolaging.2011.02.007 619

    Article  Google Scholar 

  12. Zhang Q, Zhang X, Sun A (2009) Truncated tau at D421 is associated with neurodegeneration and tangle formation in the brain of Alzheimer transgenic models. Acta Neuropathol 117(6):687–697. doi:10.1007/s00401-009-0491-6

    CAS  Article  PubMed  Google Scholar 

  13. Quintanilla RA, Matthews-Roberson TA, Dolan PJ, Johnson GV (2009) Caspase-cleaved tau expression induces mitochondrial dysfunction in immortalized cortical neurons: implications for the pathogenesis of Alzheimer disease. J Biol Chem 284(28):18754–18766. doi:10.1074/jbc.M808908200

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Kandimalla R, Reddy PH (2016) Multiple faces of dynamin-related protein 1 and its role in Alzheimer’s disease pathogenesis. Biochim Biophys Acta 1862(4):814–828. doi:10.1016/j.bbadis.2015.12.018

    CAS  Article  PubMed  Google Scholar 

  15. Reddy PH, Reddy TP, Manczak M, Calkins MJ, Shirendeb U, Mao P (2011) Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases. Brain Res Rev 67(1–2):103–118. doi:10.1016/j.brainresrev.2010.11.004

    CAS  Article  PubMed  Google Scholar 

  16. R Kandimalla, Manczak M, Fry D, Suneetha Y, Sesaki H, Reddy PH (2016) Reduced dynamin-related protein 1 protects against phosphorylated tau-induced mitochondrial dysfunction and synaptic damage in Alzheimer’s disease. Human Molecular Genetics

  17. Hauptmann S, Scherping DS, Brandt U, Schulz KL, Jendrach M, Leuner K, Eckert A, Müller WE (2009) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging 30(10):1574–1586. doi:10.1016/j.neurobiolaging.2007.12.005

    CAS  Article  PubMed  Google Scholar 

  18. Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, Ozmen L, Bluethmann H et al (2009) Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci U S A 106(47):20057–20062. doi:10.1073/pnas.0905529106

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Trushina E, Nemutlu E, Zhang S, Christensen T, Camp J, Mesa J, Siddiqui A, Tamura Y et al (2012) Defects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer’s disease. PLoS One 7(2):e32737. doi:10.1371/journal.pone.0032737

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Cabezas-Opazo FA, Vergara-Pulgar K, Perez MJ, Jara C, Osorio-Fuentealba C, Quintanilla RA (2015) Mitochondrial dysfunction contributes to the pathogenesis of Alzheimer’s disease. Oxidative Med Cell Longev 2015:509654. doi:10.1155/2015/509654

    Article  Google Scholar 

  21. Quintanilla RA, von Bernhardi R, Godoy JA, Inestrosa NC, Johnson GV (2014) Phosphorylated tau potentiates Abeta-induced mitochondrial damage in mature neurons. Neurobiol Dis 71:260–269. doi:10.1016/j.nbd.2014.08.016

    CAS  Article  PubMed  Google Scholar 

  22. Takuma H, Tomiyama T, Kuida K, Mori H (2004) Amyloid beta peptide-induced cerebral neuronal loss is mediated by caspase-3 in vivo. J Neuropathol Exp Neurol 63(3):255–261

    CAS  Article  PubMed  Google Scholar 

  23. David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, Ravid R, Drose S et al (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 280(25):23802–23814. doi:10.1074/jbc.M500356200

    CAS  Article  PubMed  Google Scholar 

  24. Lasagna-Reeves CA, Glabe CG, Kayed R (2011) Amyloid-beta annular protofibrils evade fibrillar fate in Alzheimer disease brain. J Biol Chem 286(25):22122–22130. doi:10.1074/jbc.M111.236257

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Ding H, Matthews TA, Johnson GV (2006) Site-specific phosphorylation and caspase cleavage differentially impact tau-microtubule interactions and tau aggregation. J Biol Chem 281(28):19107–19114. doi:10.1074/jbc.M511697200

    CAS  Article  PubMed  Google Scholar 

  26. Matthews-Roberson TA, Quintanilla RA, Ding H, Johnson GV (2008) Immortalized cortical neurons expressing caspase-cleaved tau are sensitized to endoplasmic reticulum stress induced cell death. Brain Res 1234:206–212. doi:10.1016/j.brainres.2008.07.111

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9(7):505–518. doi:10.1038/nrn2417

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A (2002) Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A 99(9):6364–6369. doi:10.1073/pnas.092136199

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Pallo SP, Johnson GV (2015) Tau facilitates Abeta-induced loss of mitochondrial membrane potential independent of cytosolic calcium fluxes in mouse cortical neurons. Neurosci Lett 597:32–37. doi:10.1016/j.neulet.2015.04.021

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Pallo SP, DiMaio J, Cook A, Nilsson B, Johnson GV (2016) Mechanisms of tau and Abeta-induced excitotoxicity. Brain Res 1634:119–131. doi:10.1016/j.brainres.2015.12.048

    CAS  Article  PubMed  Google Scholar 

  31. Vossel KA, Xu JC, Fomenko V, Miyamoto T, Suberbielle E, Knox JA, Ho K, Kim DH et al (2015) Tau reduction prevents Abeta-induced axonal transport deficits by blocking activation of GSK3beta. J Cell Biol 209(3):419–433. doi:10.1083/jcb.201407065

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192(1):106–113. doi:10.1016/j.bbr.2008.02.016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Verstreken P, Ly CV, Venken KJ, Koh TW, Zhou Y, Bellen HJ (2005) Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47(3):365–378. doi:10.1016/j.neuron.2005.06.018

    CAS  Article  PubMed  Google Scholar 

  34. Ly CV, Verstreken P (2006) Mitochondria at the synapse. Neuroscientist 12(4):291–299. doi:10.1177/1073858406287661

    CAS  Article  PubMed  Google Scholar 

  35. Ivannikov MV, Macleod GT (2013) Mitochondrial free Ca(2)(+) levels and their effects on energy metabolism in Drosophila motor nerve terminals. Biophys J 104(11):2353–2361. doi:10.1016/j.bpj.2013.03.064

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Rangaraju V, Calloway N, Ryan TA (2014) Activity-driven local ATP synthesis is required for synaptic function. Cell 156(4):825–835. doi:10.1016/j.cell.2013.12.042

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Reyes RC, Parpura V (2008) Mitochondria modulate Ca2+-dependent glutamate release from rat cortical astrocytes. J Neurosci 28(39):9682–9691. doi:10.1523/JNEUROSCI.3484-08.2008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Li Z, Okamoto K, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119(6):873–887. doi:10.1016/j.cell.2004.11.003

    CAS  Article  PubMed  Google Scholar 

  39. Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130(3):548–562. doi:10.1016/j.cell.2007.06.026

    CAS  Article  PubMed  Google Scholar 

  40. Kageyama Y, Zhang Z, Roda R, Fukaya M, Wakabayashi J, Wakabayashi N, Kensler TW, Reddy PH et al (2012) Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage. J Cell Biol 197(4):535–551. doi:10.1083/jcb.201110034

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Bertholet AM, Millet AM, Guillermin O, Daloyau M, Davezac N, Miquel MC, Belenguer P (2013) OPA1 loss of function affects in vitro neuronal maturation. Brain 136(Pt 5):1518–1533. doi:10.1093/brain/awt060

    Article  PubMed  Google Scholar 

  42. Williams PA, Piechota M, von Ruhland C, Taylor E, Morgan JE, Votruba M (2012) Opa1 is essential for retinal ganglion cell synaptic architecture and connectivity. Brain 135(Pt 2):493–505. doi:10.1093/brain/awr330

    Article  PubMed  Google Scholar 

  43. Kushnareva YE, Gerencser AA, Bossy B, Ju WK, White AD, Waggoner J, Ellisman MH, Perkins G et al (2013) Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity. Cell Death Differ 20(2):353–365. doi:10.1038/cdd.2012.128

    CAS  Article  PubMed  Google Scholar 

  44. Pritchard SM, Dolan PJ, Vitkus A, Johnson GV (2011) The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics. J Cell Mol Med 15(8):1621–1635. doi:10.1111/j.1582-4934.2011.01273.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Kosik KS, Joachim CL, Selkoe DJ (1986) Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A 83(11):4044–4048

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Basurto-Islas G, Luna-Munoz J, Guillozet-Bongaarts AL, Binder LI, Mena R, Garcia-Sierra F (2008) Accumulation of aspartic acid421- and glutamic acid391-cleaved tau in neurofibrillary tangles correlates with progression in Alzheimer disease. J Neuropathol Exp Neurol 67(5):470–483. doi:10.1097/NEN.0b013e31817275c7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Guillozet-Bongaarts AL, Garcia-Sierra F, Reynolds MR, Horowitz PM, Fu Y, Wang T, Cahill ME, Bigio EH et al (2005) Tau truncation during neurofibrillary tangle evolution in Alzheimer’s disease. Neurobiol Aging 26(7):1015–1022. doi:10.1016/j.neurobiolaging.2004.09.019

    CAS  Article  PubMed  Google Scholar 

  48. Means JC, Gerdes BC, Kaja S, Sumien N, Payne AJ, Stark DA, Borden PK, Price JL et al (2016) Caspase-3-dependent proteolytic cleavage of tau causes neurofibrillary tangles and results in cognitive impairment during normal aging. Neurochem Res 41(9):2278–2288. doi:10.1007/s11064-016-1942-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Kim Y, Choi H, Lee W, Park H, Kam TI, Hong SH, Nah J, Jung S et al (2016) Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model. Neurobiol Dis 87:19–28. doi:10.1016/j.nbd.2015.12.006

    CAS  Article  PubMed  Google Scholar 

  50. Ozcelik S, Sprenger F, Skachokova Z, Fraser G, Abramowski D, Clavaguera F, Probst A, Frank S et al (2016) Co-expression of truncated and full-length tau induces severe neurotoxicity. Mol Psychiatry. doi:10.1038/mp.2015.228

    PubMed  PubMed Central  Google Scholar 

  51. Wang X, Su B, Fujioka H, Zhu X (2008) Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am J Pathol 173(2):470–482. doi:10.2353/ajpath.2008.071208

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 29(28):9090–9103. doi:10.1523/JNEUROSCI.1357-09.2009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS et al (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126(1):177–189. doi:10.1016/j.cell.2006.06.025

    CAS  Article  PubMed  Google Scholar 

  54. Varanita T, Soriano ME, Romanello V, Zaglia T, Quintana-Cabrera R, Semenzato M, Menabo R, Costa V et al (2015) The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell Metab 21(6):834–844. doi:10.1016/j.cmet.2015.05.007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. de Calignon A, Fox LM, Pitstick R, Carlson GA, Bacskai BJ, Spires-Jones TL, Hyman BT (2010) Caspase activation precedes and leads to tangles. Nature 464(7292):1201–1204. doi:10.1038/nature08890

    Article  PubMed  PubMed Central  Google Scholar 

  56. Dumont M, Stack C, Elipenahli C, Jainuddin S, Gerges M, Starkova NN, Yang L, Starkov AA et al (2011) Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede tau pathology in P301S transgenic mice. FASEB J 25(11):4063–4072. doi:10.1096/fj.11-186650

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by FONDECYT #1140968 and Anillo ACT1411 (RAQ).

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Affiliations

  1. Laboratory of Neurodegenerative Diseases, Centro de Investigación Biomédica, Universidad Autónoma de Chile, El Llano Subercaseaux 2801 5to Piso, San Miguel, 8910000, Santiago, Chile

    María José Pérez, Katiana Vergara-Pulgar, Claudia Jara, Fabian Cabezas-Opazo & Rodrigo A. Quintanilla

  2. Centro de Investigación y Estudio del Consumo de Alcohol en Adolescentes (CIAA), Santiago, Chile

    Rodrigo A. Quintanilla

Authors
  1. María José Pérez
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  2. Katiana Vergara-Pulgar
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  3. Claudia Jara
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  4. Fabian Cabezas-Opazo
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  5. Rodrigo A. Quintanilla
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Correspondence to Rodrigo A. Quintanilla.

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María José Pérez and Katiana Vergara-Pulgar contributed equally to this work.

Electronic supplementary material

Figure supplementary 1

Caspase-cleaved tau expression did not affect pDrp1 and Mfn1 regulation in immortalized cortical neurons. (A) CN1.4 cells were transfected with GFP and tau constructs [GFP-T4, GFP-T42EC, GFP-T4C3, and GFP-T4C3-2EC] to determine the expression of pDrp1 using anti-pDrp1 antibody that detects Drp1 phosphorylation at S616. Representative western blot analysis from 3 independent experiments that show no significant differences in Drp1 activation by the presence of tau pathology. (B) Representative western blot image from 3 experiments of Mfn1 expression in CN1.4 cells transfected with pathological forms of tau. As well as, Mfn2, Mfn1 levels were not affected by the presence of tau pathology in these cells. In both western blot analysis the levels of β-actin were evaluated as a loading control. (GIF 857 kb)

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Figure supplementary 2

Expression levels of Drp1 and Mfn2 in CN 1.4 cells transfected with pathological forms of tau. (A), (B) are representative western blots images from CN 1.4 cells transfected with GFP and GFP-tau forms in where the levels of total Drp1 and Mfn2 were evaluated. Images includes molecular weight standard to corroborate Drp1 and Mnf2 expression in CN 1.4 cells. β-actin levels were evaluated as a loading control. Images are representative of 4 independent experiments. (GIF 918 kb)

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Pérez, M.J., Vergara-Pulgar, K., Jara, C. et al. Caspase-Cleaved Tau Impairs Mitochondrial Dynamics in Alzheimer’s Disease. Mol Neurobiol 55, 1004–1018 (2018). https://doi.org/10.1007/s12035-017-0385-x

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  • DOI: https://doi.org/10.1007/s12035-017-0385-x

Keywords

  • Tau
  • Mitochondria
  • Alzheimer’s disease
  • Neurodegeneration
  • Opa1