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Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo

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Abstract

It has been hypothesised that tau protein, when hyper-phosphorylated as in Alzheimer’s disease (AD), does not bind effectively to microtubules and is no longer able to stabilise them; thus microtubules break down, and axonal transport can no longer proceed efficiently in affected brain regions in AD and related tauopathies (tau-microtubule hypothesis). We have used Drosophila models of tauopathy to test all components of this hypothesis in vivo. We have previously shown that upon expression of human 0N3R tau in Drosophila motor neurons it becomes highly phosphorylated, resulting in disruptions to both axonal transport and synaptic function which culminate in behavioural phenotypes. We now show that the mechanism by which the human tau mediates these effects is twofold: first, as predicted by the tau-microtubule hypothesis, the highly phosphorylated tau exhibits significantly reduced binding to microtubules; and second, it participates in a pathogenic interaction with the endogenous normal Drosophila tau and sequesters it away from microtubules. This causes disruption of the microtubular cytoskeleton as evidenced by a reduction in the numbers of intact correctly-aligned microtubules and the appearance of microtubules that are not correctly oriented within the axon. These deleterious effects of human tau are phosphorylation dependent because treatment with LiCl to suppress tau phosphorylation increases microtubule binding of both human and Drosophila tau and restores cytoskeletal integrity. Notably, all these phospho-tau-mediated phenotypes occur in the absence of tau filament/neurofibrillary tangle formation or neuronal death, and may thus constitute the mechanism by which hyper-phosphorylated tau disrupts neuronal function and contributes to cognitive impairment prior to neuronal death in the early stages of tauopathies.

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References

  1. Alonso AC, Zaidi T, Grundke-Iqbal I et al (1994) Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci USA 91:5562–5566

    Article  CAS  PubMed  Google Scholar 

  2. Alonso AD, Grundke-Iqbal I, Barra HS et al (1997) Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc Natl Acad Sci USA 94:298–303

    Article  CAS  PubMed  Google Scholar 

  3. Alonso Adel C, Li B, Grundke-Iqbal I et al (2006) Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. Proc Natl Acad Sci USA 103:8864–8869

    Article  PubMed  Google Scholar 

  4. Alonso Adel C, Mederlyova A, Novak M et al (2004) Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem 279:34873–34881

    Article  PubMed  Google Scholar 

  5. Bramblett GT, Goedert M, Jakes R et al (1993) Abnormal tau phosphorylation at Ser396 in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding. Neuron 10:1089–1099

    Article  CAS  PubMed  Google Scholar 

  6. Cash AD, Aliev G, Siedlak SL et al (2003) Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation. Am J Pathol 162:1623–1627

    CAS  PubMed  Google Scholar 

  7. Chatterjee S, Sang TK, Lawless GM et al (2009) Dissociation of tau toxicity and phosphorylation: role of GSK-3beta, MARK and Cdk5 in a Drosophila model. Hum Mol Genet 18:164–177

    Article  CAS  PubMed  Google Scholar 

  8. Chee FC, Mudher A, Cuttle MF (2005) Over-expression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions. Neurobiol Dis 20:918–928

    Article  CAS  PubMed  Google Scholar 

  9. Cleveland DW, Hwo SY, Kirschner MW (1977) Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J Mol Biol 116:227–247

    Article  CAS  PubMed  Google Scholar 

  10. Coleman PD, Yao PJ (2003) Synaptic slaughter in Alzheimer’s disease. Neurobiol Aging 24:1023–1027

    Article  CAS  PubMed  Google Scholar 

  11. Dayanandan R, Van Slegtenhorst M, Mack TG et al (1999) Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation. FEBS Lett 446:228–232

    Article  CAS  PubMed  Google Scholar 

  12. Dixit R, Ross JL, Goldman YE et al (2008) Differential regulation of dynein and kinesin motor proteins by tau. Science 319:1086–1089

    Article  CAS  PubMed  Google Scholar 

  13. Doerflinger H, Benton R, Shulman JM et al (2003) The role of PAR-1 in regulating the polarised microtubule cytoskeleton in the Drosophila follicular epithelium. Development 130:3965–3975

    Article  CAS  PubMed  Google Scholar 

  14. Drechsel DN, Hyman AA, Cobb MH et al (1992) Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell 3:1141–1154

    CAS  PubMed  Google Scholar 

  15. Feinstein SC, Wilson L (2005) Inability of tau to properly regulate neuronal microtubule dynamics: a loss-of-function mechanism by which tau might mediate neuronal cell death. Biochim Biophys Acta 1739:268–279

    CAS  PubMed  Google Scholar 

  16. Grundke-Iqbal I, Iqbal K, Tung YC et al (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917

    Article  CAS  PubMed  Google Scholar 

  17. Gustke N, Trinczek B, Biernat J et al (1994) Domains of tau protein and interactions with microtubules. Biochemistry 33:9511–9522

    Article  CAS  PubMed  Google Scholar 

  18. Han D, Qureshi HY, Lu Y et al (2009) Familial FTDP-17 missense mutations inhibit microtubule assembly-promoting activity of tau by increasing phosphorylation at Ser202 in vitro. J Biol Chem 284:13422–13433

    Article  CAS  PubMed  Google Scholar 

  19. Hasegawa M, Smith MJ, Goedert M (1998) Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett 437:207–210

    Article  CAS  PubMed  Google Scholar 

  20. Iqbal K, Alonso Adel C, Grundke-Iqbal I (2008) Cytosolic abnormally hyperphosphorylated tau but not paired helical filaments sequester normal MAPs and inhibit microtubule assembly. J Alzheimers Dis 14:365–370

    PubMed  Google Scholar 

  21. Iqbal K, Grundke-Iqbal I, Zaidi T et al (1986) Defective brain microtubule assembly in Alzheimer’s disease. Lancet 2:421–426

    Article  CAS  PubMed  Google Scholar 

  22. Iqbal K, Liu F, Gong CX et al (2009) Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 118:53–69

    Article  CAS  PubMed  Google Scholar 

  23. Ishihara T, Hong M, Zhang B et al (1999) Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24:751–762

    Article  CAS  PubMed  Google Scholar 

  24. Ishihara T, Zhang B, Higuchi M et al (2001) Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice. Am J Pathol 158:555–562

    CAS  PubMed  Google Scholar 

  25. Li B, Chohan MO, Grundke-Iqbal I et al (2007) Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau. Acta Neuropathol 113:501–511

    Article  CAS  PubMed  Google Scholar 

  26. Liu SJ, Zhang JY, Li HL et al (2004) Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain. J Biol Chem 279:50078–50088

    Article  CAS  PubMed  Google Scholar 

  27. Lovestone S, Davis DR, Webster MT et al (1999) Lithium reduces tau phosphorylation: effects in living cells and in neurons at therapeutic concentrations. Biol Psychiatry 45:995–1003

    Article  CAS  PubMed  Google Scholar 

  28. Lovestone S, Hartley CL, Pearce J et al (1996) Phosphorylation of tau by glycogen synthase kinase-3 beta in intact mammalian cells: the effects on the organization and stability of microtubules. Neuroscience 73:1145–1157

    Article  CAS  PubMed  Google Scholar 

  29. Lovestone S, Reynolds CH, Latimer D et al (1994) Alzheimer’s disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr Biol 4:1077–1086

    Article  CAS  PubMed  Google Scholar 

  30. Mandelkow EM, Biernat J, Drewes G et al (1995) Tau domains, phosphorylation, and interactions with microtubules. Neurobiol Aging 16:355–362 discussion 362–363

    Article  CAS  PubMed  Google Scholar 

  31. Mandelkow EM, Thies E, Trinczek B et al (2004) MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons. J Cell Biol 167:99–110

    Article  CAS  PubMed  Google Scholar 

  32. Mocanu MM, Nissen A, Eckermann K et al (2008) The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J Neurosci 28:737–748

    Article  CAS  PubMed  Google Scholar 

  33. Mudher A, Shepherd D, Newman TA et al (2004) GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry 9:522–530

    Article  CAS  PubMed  Google Scholar 

  34. Murrell JR, Spillantini MG, Zolo P et al (1999) Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits. J Neuropathol Exp Neurol 58:1207–1226

    Article  CAS  PubMed  Google Scholar 

  35. Nagiec EW, Sampson KE, Abraham I (2001) Mutated tau binds less avidly to microtubules than wildtype tau in living cells. J Neurosci Res 63:268–275

    Article  CAS  PubMed  Google Scholar 

  36. Oddo S, Vasilevko V, Caccamo A et al (2006) Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. J Biol Chem 281:39413–39423

    Article  CAS  PubMed  Google Scholar 

  37. Planel E, Krishnamurthy P, Miyasaka T et al (2008) Anesthesia-induced hyperphosphorylation detaches 3-repeat tau from microtubules without affecting their stability in vivo. J Neurosci 28:12798–12807

    Article  CAS  PubMed  Google Scholar 

  38. Praprotnik D, Smith MA, Richey PL et al (1996) Filament heterogeneity within the dystrophic neurites of senile plaques suggests blockage of fast axonal transport in Alzheimer’s disease. Acta Neuropathol 91:226–235

    Article  CAS  PubMed  Google Scholar 

  39. Preuss U, Biernat J, Mandelkow EM et al (1997) The ‘jaws’ model of tau-microtubule interaction examined in CHO cells. J Cell Sci 110(Pt 6):789–800

    CAS  PubMed  Google Scholar 

  40. Santarella RA, Skiniotis G, Goldie KN et al (2004) Surface-decoration of microtubules by human tau. J Mol Biol 339:539–553

    Article  CAS  PubMed  Google Scholar 

  41. Stambolic V, Ruel L, Woodgett JR (1996) Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol 6:1664–1668

    Article  CAS  PubMed  Google Scholar 

  42. Suzuki K, Terry RD (1967) Fine structural localization of acid phosphatase in senile plaques in Alzheimer’s presenile dementia. Acta Neuropathol 8:276–284

    Article  CAS  PubMed  Google Scholar 

  43. Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580

    Article  CAS  PubMed  Google Scholar 

  44. Trinczek B, Biernat J, Baumann K et al (1995) Domains of tau protein, differential phosphorylation, and dynamic instability of microtubules. Mol Biol Cell 6:1887–1902

    CAS  PubMed  Google Scholar 

  45. Trinczek B, Ebneth A, Mandelkow EM et al (1999) Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles. J Cell Sci 112(14):2355–2367

    CAS  PubMed  Google Scholar 

  46. Ubhi KK, Shaibah H, Newman TA et al (2007) A comparison of the neuronal dysfunction caused by Drosophila tau and human tau in a Drosophila model of tauopathies. Invert Neurosci 7:165–171

    Article  CAS  PubMed  Google Scholar 

  47. Wang JZ, Gong CX, Zaidi T et al (1995) Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J Biol Chem 270:4854–4860

    Article  CAS  PubMed  Google Scholar 

  48. Wang JZ, Grundke-Iqbal I, Iqbal K (1996) Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1. Brain Res Mol Brain Res 38:200–208

    Article  CAS  PubMed  Google Scholar 

  49. Williams DW, Tyrer M, Shepherd D (2000) Tau and tau reporters disrupt central projections of sensory neurons in Drosophila. J Comp Neurol 428:630–640

    Article  CAS  PubMed  Google Scholar 

  50. Wittmann CW, Wszolek MF, Shulman JM et al (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293:711–714

    Article  CAS  PubMed  Google Scholar 

  51. Wood JG, Mirra SS, Pollock NJ et al (1986) Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau). Proc Natl Acad Sci USA 83:4040–4043

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank Professor St. Johnston of Cambridge University for the Drosophila tau antibody, and Dr. Hansjürgen Schuppe and Joanne Bailey for assistance with confocal microscopy. Funding was provided by the Alzheimer’s Society, UK.

Conflict of interest statement

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. School of Biological Sciences, University of Southampton, Southampton, SO16 7PS, UK

    Catherine M. Cowan, Torsten Bossing, David Shepherd & Amritpal Mudher

  2. Biomedical Imaging Unit, Southampton General Hospital, Southampton, SO16 6YD, UK

    Anton Page

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  1. Catherine M. Cowan
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Correspondence to Amritpal Mudher.

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Cowan, C.M., Bossing, T., Page, A. et al. Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo. Acta Neuropathol 120, 593–604 (2010). https://doi.org/10.1007/s00401-010-0716-8

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  • DOI: https://doi.org/10.1007/s00401-010-0716-8

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