Skip to main content
SpringerLink
Log in
Book cover

Tau Biology pp 81–95Cite as

Tau and Axonal Transport Misregulation in Tauopathies

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1184))

Abstract

Tau is a microtubule-associated protein that is involved in both normal and pathological processes in neurons. Since the discovery and characterization of tau over 40 years ago, our understanding of tau’s normal functions and toxic roles in neurodegenerative tauopathies has continued to expand. Fast axonal transport is a critical process for maintaining axons and functioning synapses, critical subcellular compartments underlying neuronal connectivity. Signs of fast axonal transport disruption are pervasive in Alzheimer’s disease and other tauopathies and various mechanisms have been proposed for regulation of fast axonal transport by tau. Post-translational modifications of tau including phosphorylation at specific sites, FTDP-17 point mutations, and oligomerization, confer upon tau a toxic effect on fast axonal transport. Consistent with the well-established dependence of axons on fast axonal transport, these disease-related modifications are closely associated temporally and spatially with axonal degeneration in the early disease stages. These factors position tau as a potentially critical factor mediating the disruption of fast axonal transport that precedes synaptic dysfunction and axonal degeneration at later disease stages. In this chapter, we review the evidence that tau affects fast axonal transport and examine several potential mechanisms proposed to underlie this toxicity.

Authors Benjamin Combs and Rebecca L. Mueller have equally contributed to this chapter.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Adalbert R, Milde S, Durrant C, Ando K, Stygelbout V, Yilmaz Z, Gould S, Brion JP, Coleman MP. Interaction between a MAPT variant causing frontotemporal dementia and mutant APP affects axonal transport. Neurobiol Aging. 2018;68:68–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ahmed Z, Josephs KA, Gonzalez J, DelleDonne A, Dickson DW. Clinical and neuropathologic features of progressive supranuclear palsy with severe pallido-nigro-luysial degeneration and axonal dystrophy. Brain. 2008;131:460–72.

    Article  PubMed  Google Scholar 

  3. Amaratunga A, Morin PJ, Kosik KS, Fine RE. Inhibition of kinesin synthesis and rapid anterograde axonal transport in vivo by an antisense oligonucleotide. J Biol Chem. 1993;268:17427–30.

    CAS  PubMed  Google Scholar 

  4. Beevers JE, Lai MC, Collins E, Booth HDE, Zambon F, Parkkinen L, Vowles J, Cowley SA, Wade-Martins R, Caffrey TM. MAPT genetic variation and neuronal maturity Alter isoform expression affecting axonal transport in iPSC-derived dopamine neurons. Stem Cell Rep. 2017;9:587–99.

    Article  CAS  Google Scholar 

  5. Binder LI, Frankfurter A, Rebhun LI. The distribution of tau in the mammalian central nervous system. J Cell Biol. 1985;101:1371–8.

    Article  CAS  PubMed  Google Scholar 

  6. Black MM. Axonal transport: the orderly motion of axonal structures. Methods Cell Biol. 2016;131:1–19.

    Article  PubMed  Google Scholar 

  7. Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging. 1995;16:271–8.. discussion 278-284

    Article  CAS  PubMed  Google Scholar 

  8. Braak E, Braak H, Mandelkow EM. A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol (Berl). 1994;87:554–67.

    Article  CAS  Google Scholar 

  9. Brady ST, Morfini GA. Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases. Neurobiol Dis. 2017;105:273–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Brady ST, Sperry AO. Biochemical and functional diversity of microtubule motors in the nervous system. Curr Opin Neurobiol. 1995;5:551–8.

    Article  CAS  PubMed  Google Scholar 

  11. Brady ST, Lasek RJ, Allen RD. Fast axonal transport in extruded axoplasm from squid giant axon. Science. 1982;218:1129–31.

    Article  CAS  PubMed  Google Scholar 

  12. Bramblett GT, Goedert M, Jakes R, Merrick SE, Trojanowski JQ, Lee VM. Abnormal tau phosphorylation at Ser396 in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding. Neuron. 1993;10:1089–99.

    Article  CAS  PubMed  Google Scholar 

  13. Buee L, Delacourte A. Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick’s disease. Brain Pathol. 1999;9:681–93.

    Article  CAS  PubMed  Google Scholar 

  14. Butler VJ, Salazar DA, Soriano-Castell D, Alves-Ferreira M, Dennissen FJA, Vohra M, Oses-Prieto JA, Li KH, Wang AL, Jing B, Li B, Groisman A, Gutierrez E, Mooney S, Burlingame AL, Ashrafi K, Mandelkow EM, Encalada SE, Kao AW. Tau/MAPT disease-associated variant A152T alters tau function and toxicity via impaired retrograde axonal transport. Hum Mol Genet. 2018;

    Google Scholar 

  15. Carmel G, Mager EM, Binder LI, Kuret J. The structural basis of monoclonal antibody Alz50’s selectivity for Alzheimer’s disease pathology. J Biol Chem. 1996;271:32789–95.

    Article  CAS  PubMed  Google Scholar 

  16. Combs B, Kanaan NM. Exposure of the amino terminus of tau is a pathological event in multiple Tauopathies. Am J Pathol. 2017;187:1222–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Combs B, Hamel C, Kanaan NM. Pathological conformations involving the amino terminus of tau occur early in Alzheimer’s disease and are differentially detected by monoclonal antibodies. Neurobiol Dis. 2016;94:18–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cox K, Combs B, Abdelmesih B, Morfini G, Brady ST, Kanaan NM. Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition. Neurobiol Aging. 2016;47:113–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. DeBerg HA, Blehm BH, Sheung J, Thompson AR, Bookwalter CS, Torabi SF, Schroer TA, Berger CL, Lu Y, Trybus KM, Selvin PR. Motor domain phosphorylation modulates kinesin-1 transport. J Biol Chem. 2013;288:32612–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. DeBoer SR, You Y, Szodorai A, Kaminska A, Pigino G, Nwabuisi E, Wang B, Estrada-Hernandez T, Kins S, Brady ST, Morfini G. Conventional kinesin holoenzymes are composed of heavy and light chain homodimers. Biochemistry. 2008;47:4535–43.

    Article  CAS  PubMed  Google Scholar 

  21. DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol. 1990;27:457–64.

    Article  CAS  PubMed  Google Scholar 

  22. Dixit R, Ross JL, Goldman YE, Holzbaur EL. Differential regulation of dynein and kinesin motor proteins by tau. Science. 2008;319:1086–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E. Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer’s disease. J Cell Biol. 1998;143:777–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Egloff MP, Johnson DF, Moorhead G, Cohen PT, Cohen P, Barford D. Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1. EMBO J. 1997;16:1876–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ghoshal N, Garcia-Sierra F, Wuu J, Leurgans S, Bennett DA, Berry RW, Binder LI. Tau conformational changes correspond to impairments of episodic memory in mild cognitive impairment and Alzheimer’s disease. Exp Neurol. 2002;177:475–93.

    Article  CAS  PubMed  Google Scholar 

  26. Gilley J, Seereeram A, Ando K, Mosely S, Andrews S, Kerschensteiner M, Misgeld T, Brion JP, Anderton B, Hanger DP, Coleman MP. Age-dependent axonal transport and locomotor changes and tau hypophosphorylation in a “P301L” tau knockin mouse. Neurobiol Aging. 2012;33:621 e621–15.

    Article  CAS  Google Scholar 

  27. Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron. 1992;8:159–68.

    Article  CAS  PubMed  Google Scholar 

  28. Gong CX, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, Iqbal K. Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease. J Biol Chem. 2000;275:5535–44.

    Article  CAS  PubMed  Google Scholar 

  29. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986a;83:4913–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem. 1986b;261:6084–9.

    CAS  PubMed  Google Scholar 

  31. Guillozet-Bongaarts AL, Garcia-Sierra F, Reynolds MR, Horowitz PM, Fu Y, Wang T, Cahill ME, Bigio EH, Berry RW, Binder LI. Tau truncation during neurofibrillary tangle evolution in Alzheimer’s disease. Neurobiol Aging. 2005;26:1015–22.

    Article  CAS  PubMed  Google Scholar 

  32. Guillozet-Bongaarts AL, Cahill ME, Cryns VL, Reynolds MR, Berry RW, Binder LI. Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo. J Neurochem. 2006;97:1005–14.

    Article  CAS  PubMed  Google Scholar 

  33. Hauw JJ, Verny M, Delaere P, Cervera P, He Y, Duyckaerts C. Constant neurofibrillary changes in the neocortex in progressive supranuclear palsy. Basic differences with Alzheimer’s disease and aging. Neurosci Lett. 1990;119:182–6.

    Article  CAS  PubMed  Google Scholar 

  34. Horowitz PM, Patterson KR, Guillozet-Bongaarts AL, Reynolds MR, Carroll CA, Weintraub ST, Bennett DA, Cryns VL, Berry RW, Binder LI. Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer’s disease. J Neurosci. 2004;24:7895–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hutton M, et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393:702–5.

    Article  CAS  PubMed  Google Scholar 

  36. Ikeda K, Akiyama H, Haga C, Kondo H, Arima K, Oda T. Argyrophilic thread-like structure in corticobasal degeneration and supranuclear palsy. Neurosci Lett. 1994;174:157–9.

    Article  CAS  PubMed  Google Scholar 

  37. Ittner LM, Ke YD, Gotz J. Phosphorylated tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease. J Biol Chem. 2009;284:20909–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jeganathan S, von Bergen M, Brutlach H, Steinhoff HJ, Mandelkow E. Global hairpin folding of tau in solution. Biochemistry. 2006;45:2283–93.

    Article  CAS  PubMed  Google Scholar 

  39. Jeganathan S, Hascher A, Chinnathambi S, Biernat J, Mandelkow EM, Mandelkow E. Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of tau and generates a pathological (MC-1) conformation. J Biol Chem. 2008;283:32066–76.

    Article  CAS  PubMed  Google Scholar 

  40. Kanaan NM, Morfini GA, LaPointe NE, Pigino GF, Patterson KR, Song Y, Andreadis A, Fu Y, Brady ST, Binder LI. Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J Neurosci. 2011;31:9858–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kanaan NM, Morfini G, Pigino G, LaPointe NE, Andreadis A, Song Y, Leitman E, Binder LI, Brady ST. Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport. Neurobiol Aging. 2012;33(826):e815–30.

    Google Scholar 

  42. Kanaan NM, Pigino GF, Brady ST, Lazarov O, Binder LI, Morfini GA. Axonal degeneration in Alzheimer’s disease: when signaling abnormalities meet the axonal transport system. Exp Neurol. 2013;246:44–53.

    Article  CAS  PubMed  Google Scholar 

  43. Kanaan NM, Cox K, Alvarez VE, Stein TD, Poncil S, McKee AC. Characterization of early pathological tau conformations and phosphorylation in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2016;75:19–34.

    Article  CAS  PubMed  Google Scholar 

  44. Kang M, Baker L, Song Y, Brady ST, Morfini G. Biochemical analysis of axon-specific phosphorylation events using isolated squid axoplasms. Methods Cell Biol. 2016;131:199–216.

    Article  PubMed  Google Scholar 

  45. Kneynsberg A, Combs B, Christensen K, Morfini G, Kanaan NM. Axonal degeneration in Tauopathies: disease relevance and underlying mechanisms. Front Neurosci. 2017;11:572.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kovacs GG. Invited review: neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol. 2015;41:3–23.

    Article  CAS  PubMed  Google Scholar 

  47. Kowall NW, Kosik KS. Axonal disruption and aberrant localization of tau protein characterize the neuropil pathology of Alzheimer’s disease. Ann Neurol. 1987;22:639–43.

    Article  CAS  PubMed  Google Scholar 

  48. Kraus MF, Susmaras T, Caughlin BP, Walker CJ, Sweeney JA, Little DM. White matter integrity and cognition in chronic traumatic brain injury: a diffusion tensor imaging study. Brain. 2007;130:2508–19.

    Article  PubMed  Google Scholar 

  49. Kreutzberg GW. Neuronal dynamics and axonal flow. IV. Blockage of intra-axonal enzyme transport by colchicine. Proc Natl Acad Sci U S A. 1969;62:722–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. LaPointe NE, Morfini G, Pigino G, Gaisina IN, Kozikowski AP, Binder LI, Brady ST. The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity. J Neurosci Res. 2009;87:440–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lasek RJ, Garner JA, Brady ST. Axonal transport of the cytoplasmic matrix. J Cell Biol. 1984;99:212s–21s.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liao H, Li Y, Brautigan DL, Gundersen GG. Protein phosphatase 1 is targeted to microtubules by the microtubule-associated protein tau. J Biol Chem. 1998;273:21901–8.

    Article  CAS  PubMed  Google Scholar 

  53. Ling H. Untangling the tauopathies: current concepts of tau pathology and neurodegeneration. Parkinsonism Relat Disord. 2018;46(Suppl 1):S34–8.

    Article  PubMed  Google Scholar 

  54. Mandelkow EM, Stamer K, Vogel R, Thies E, Mandelkow E. Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses. Neurobiol Aging. 2003;24:1079–85.

    Article  CAS  PubMed  Google Scholar 

  55. Martin L, Latypova X, Terro F. Post-translational modifications of tau protein: implications for Alzheimer’s disease. Neurochem Int. 2011;58:458–71.

    Article  CAS  PubMed  Google Scholar 

  56. McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, Santini VE, Lee HS, Kubilus CA, Stern RA. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68:709–35.

    Article  PubMed  Google Scholar 

  57. McVicker DP, Chrin LR, Berger CL. The nucleotide-binding state of microtubules modulates kinesin processivity and the ability of tau to inhibit kinesin-mediated transport. J Biol Chem. 2011;286:42873–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mephon-Gaspard A, Boca M, Pioche-Durieu C, Desforges B, Burgo A, Hamon L, Pietrement O, Pastre D. Role of tau in the spatial organization of axonal microtubules: keeping parallel microtubules evenly distributed despite macromolecular crowding. Cell Mol Life Sci. 2016;73:3745–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Miki H, Okada Y, Hirokawa N. Analysis of the kinesin superfamily: insights into structure and function. Trends Cell Biol. 2005;15:467–76.

    Article  CAS  PubMed  Google Scholar 

  60. Moreno H, Morfini G, Buitrago L, Ujlaki G, Choi S, Yu E, Moreira JE, Avila J, Brady ST, Pant H, Sugimori M, Llinas RR. Tau pathology-mediated presynaptic dysfunction. Neuroscience. 2016;325:30–8.

    Article  CAS  PubMed  Google Scholar 

  61. Morfini G, Szebenyi G, Elluru R, Ratner N, Brady ST. Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J. 2002;21:281–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Morfini G, Szebenyi G, Brown H, Pant HC, Pigino G, DeBoer S, Beffert U, Brady ST. A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons. EMBO J. 2004;23:2235–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Morfini G, Pigino G, Mizuno N, Kikkawa M, Brady ST. Tau binding to microtubules does not directly affect microtubule-based vesicle motility. J Neurosci Res. 2007;85:2620–30.

    Article  CAS  PubMed  Google Scholar 

  64. Morfini GA, You YM, Pollema SL, Kaminska A, Liu K, Yoshioka K, Bjorkblom B, Coffey ET, Bagnato C, Han D, Huang CF, Banker G, Pigino G, Brady ST. Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin. Nat Neurosci. 2009a;12:864–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Morfini GA, Burns M, Binder LI, Kanaan NM, LaPointe N, Bosco DA, Brown RH Jr, Brown H, Tiwari A, Hayward L, Edgar J, Nave KA, Garberrn J, Atagi Y, Song Y, Pigino G, Brady ST. Axonal transport defects in neurodegenerative diseases. J Neurosci. 2009b;29:12776–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Morfini GA, Bosco DA, Brown H, Gatto R, Kaminska A, Song Y, Molla L, Baker L, Marangoni MN, Berth S, Tavassoli E, Bagnato C, Tiwari A, Hayward LJ, Pigino GF, Watterson DM, Huang CF, Banker G, Brown RH Jr, Brady ST. Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. PLoS One. 2013;8:e65235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Morfini G, Schmidt N, Weissmann C, Pigino G, Kins S. Conventional kinesin: biochemical heterogeneity and functional implications in health and disease. Brain Res Bull. 2016;126:347–53.

    Article  CAS  PubMed  Google Scholar 

  68. Mudher A, Shepherd D, Newman TA, Mildren P, Jukes JP, Squire A, Mears A, Drummond JA, Berg S, MacKay D, Asuni AA, Bhat R, Lovestone S. GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry. 2004;9:522–30.

    Article  CAS  PubMed  Google Scholar 

  69. Mukrasch MD, Bibow S, Korukottu J, Jeganathan S, Biernat J, Griesinger C, Mandelkow E, Zweckstetter M. Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol. 2009;7:e34.

    Article  CAS  PubMed  Google Scholar 

  70. Padovani A, Borroni B, Brambati SM, Agosti C, Broli M, Alonso R, Scifo P, Bellelli G, Alberici A, Gasparotti R, Perani D. Diffusion tensor imaging and voxel based morphometry study in early progressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 2006;77:457–63.

    Article  CAS  PubMed  Google Scholar 

  71. Patterson KR, Remmers C, Fu Y, Brooker S, Kanaan NM, Vana L, Ward S, Reyes JF, Philibert K, Glucksman MJ, Binder LI. Characterization of prefibrillar tau oligomers in vitro and in Alzheimer disease. J Biol Chem. 2011;286:23063–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L, LaDu M, Busciglio J, Brady S. Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci U S A. 2009;106:5907–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pir GJ, Choudhary B, Mandelkow E, Mandelkow EM. Tau mutant A152T, a risk factor for FTD/PSP, induces neuronal dysfunction and reduced lifespan independently of aggregation in a C. elegans Tauopathy model. Mol Neurodegener. 2016;11:33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Probst A, Tolnay M, Langui D, Goedert M, Spillantini MG. Pick’s disease: hyperphosphorylated tau protein segregates to the somatoaxonal compartment. Acta Neuropathol (Berl). 1996;92:588–96.

    Article  CAS  Google Scholar 

  75. Ray K, Perez SE, Yang Z, Xu J, Ritchings BW, Steller H, Goldstein LS. Kinesin-II is required for axonal transport of choline acetyltransferase in Drosophila. J Cell Biol. 1999;147:507–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Reck-Peterson SL, Redwine WB, Vale RD, Carter AP. The cytoplasmic dynein transport machinery and its many cargoes. Nat Rev Mol Cell Biol. 2018;19:382–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rovelet-Lecrux A, Lecourtois M, Thomas-Anterion C, Le Ber I, Brice A, Frebourg T, Hannequin D, Campion D. Partial deletion of the MAPT gene: a novel mechanism of FTDP-17. Hum Mutat. 2009;30:E591–602.

    Article  PubMed  Google Scholar 

  78. Roy S. Seeing the unseen: the hidden world of slow axonal transport. Neuroscientist RevJ Bring Neurobiol Neurol Psychiat. 2014;20:71–81.

    Google Scholar 

  79. Roy S, Zhang B, Lee VM, Trojanowski JQ. Axonal transport defects: a common theme in neurodegenerative diseases. Acta Neuropathol. 2005;109:5–13.

    Article  PubMed  Google Scholar 

  80. Sealey MA, Vourkou E, Cowan CM, Bossing T, Quraishe S, Grammenoudi S, Skoulakis EMC, Mudher A. Distinct phenotypes of three-repeat and four-repeat human tau in a transgenic model of tauopathy. Neurobiol Dis. 2017;105:74–83.

    Article  CAS  PubMed  Google Scholar 

  81. Seitz A, Kojima H, Oiwa K, Mandelkow EM, Song YH, Mandelkow E. Single-molecule investigation of the interference between kinesin, tau and MAP 2c. EMBO J. 2002;21:4896–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sengupta A, Kabat J, Novak M, Wu Q, Grundke-Iqbal I, Iqbal K. Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys. 1998;357:299–309.

    Article  CAS  PubMed  Google Scholar 

  83. Sergeant N, Wattez A, Delacourte A. Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively “exon 10” isoforms. J Neurochem. 1999;72:1243–9.

    Article  CAS  PubMed  Google Scholar 

  84. Simic G, Babic Leko M, Wray S, Harrington C, Delalle I, Jovanov-Milosevic N, Bazadona D, Buee L, de Silva R, Di Giovanni G, Wischik C, Hof PR. Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other Tauopathies, and possible neuroprotective strategies. Biomol Ther. 2016;6:6.

    Google Scholar 

  85. Song Y, Kang M, Morfini G, Brady ST. Fast axonal transport in isolated axoplasm from the squid giant axon. Methods Cell Biol. 2016;131:331–48.

    Article  PubMed  Google Scholar 

  86. Soppina V, Verhey KJ. The family-specific K-loop influences the microtubule on-rate but not the superprocessivity of kinesin-3 motors. Mol Biol Cell. 2014;25:2161–70.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol. 2002;156:1051–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Stenoien DL, Brady ST. Immunochemical analysis of kinesin light chain function. Mol Biol Cell. 1997;8:675–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Stern JL, Lessard DV, Hoeprich GJ, Morfini GA, Berger CL. Phosphoregulation of tau modulates inhibition of kinesin-1 motility. Mol Biol Cell. 2017;28:1079–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Szodorai A, Kuan YH, Hunzelmann S, Engel U, Sakane A, Sasaki T, Takai Y, Kirsch J, Muller U, Beyreuther K, Brady S, Morfini G, Kins S. APP anterograde transport requires Rab3A GTPase activity for assembly of the transport vesicle. J Neurosci. 2009;29:14534–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Talmat-Amar Y, Arribat Y, Parmentier ML. Vesicular axonal transport is modified in vivo by tau deletion or overexpression in Drosophila. Int J Mol Sci. 2018;19

    Google Scholar 

  92. Tanaka Y, Kanai Y, Okada Y, Nonaka S, Takeda S, Harada A, Hirokawa N. Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell. 1998;93:1147–58.

    Article  CAS  PubMed  Google Scholar 

  93. Tiernan CT, Combs B, Cox K, Morfini G, Brady ST, Counts SE, Kanaan NM. Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport. Exp Neurol. 2016;283:318–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Tiernan CT, Ginsberg SD, He B, Ward SM, Guillozet-Bongaarts AL, Kanaan NM, Mufson EJ, Counts SE. Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer’s disease. Neurobiol Dis. 2018;117:125–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Trabzuni D, Wray S, Vandrovcova J, Ramasamy A, Walker R, Smith C, Luk C, Gibbs JR, Dillman A, Hernandez DG, Arepalli S, Singleton AB, Cookson MR, Pittman AM, de Silva R, Weale ME, Hardy J, Ryten M. MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies. Hum Mol Genet. 2012;21:4094–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Trinczek B, Ebneth A, Mandelkow EM, Mandelkow E. Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles. J Cell Sci. 1999;112(Pt 14):2355–67.

    CAS  PubMed  Google Scholar 

  97. Tsai MY, Morfini G, Szebenyi G, Brady ST. Release of kinesin from vesicles by hsc70 and regulation of fast axonal transport. Mol Biol Cell. 2000;11:2161–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Uchida A, Alami NH, Brown A. Tight functional coupling of kinesin-1A and dynein motors in the bidirectional transport of neurofilaments. Mol Biol Cell. 2009;20:4997–5006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Uryu K, Chen XH, Martinez D, Browne KD, Johnson VE, Graham DI, Lee VM, Trojanowski JQ, Smith DH. Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans. Exp Neurol. 2007;208:185–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Vershinin M, Carter BC, Razafsky DS, King SJ, Gross SP. Multiple-motor based transport and its regulation by tau. Proc Natl Acad Sci U S A. 2007;104:87–92.

    Article  CAS  PubMed  Google Scholar 

  101. Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, Cui B, Mucke L. Tau reduction prevents Abeta-induced defects in axonal transport. Science. 2010;330:198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Vossel KA, Xu JC, Fomenko V, Miyamoto T, Suberbielle E, Knox JA, Ho K, Kim DH, Yu GQ, Mucke L. Tau reduction prevents Abeta-induced axonal transport deficits by blocking activation of GSK3beta. J Cell Biol. 2015;209:419–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016;17:5–21.

    Article  PubMed  CAS  Google Scholar 

  104. Ward SM, Himmelstein DS, Lancia JK, Fu Y, Patterson KR, Binder LI. TOC1: characterization of a selective oligomeric tau antibody. J Alzheimers Dis. 2013;37:593–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A. 1975;72:1858–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wong CW, Quaranta V, Glenner GG. Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related. Proc Natl Acad Sci U S A. 1985;82:8729–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wood JG, Mirra SS, Pollock NJ, Binder LI. Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau) [published erratum appears in Proc Natl Acad Sci U S A 1986 Dec;83(24):9773]. Proc Natl Acad Sci U S A. 1986;83:4040–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Yamakawa K, Takanashi M, Watanabe M, Nakamura N, Kobayashi T, Hasegawa M, Mizuno Y, Tanaka S, Mori H. Pathological and biochemical studies on a case of pick disease with severe white matter atrophy. Neuropathol Off J Jpn Soc Neuropathol. 2006;26:586–91.

    Article  Google Scholar 

  109. Yoshida M. Cellular tau pathology and immunohistochemical study of tau isoforms in sporadic tauopathies. Neuropathol Off J Jpn Soc Neuropathol. 2006;26:457–70.

    Article  Google Scholar 

  110. Yuan A, Kumar A, Peterhoff C, Duff K, Nixon RA. Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J Neurosci. 2008;28:1682–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhang Y, Walter R, Ng P, Luong PN, Dutt S, Heuer H, Rojas-Rodriguez JC, Tsai R, Litvan I, Dickerson BC, Tartaglia MC, Rabinovici G, Miller BL, Rosen HJ, Schuff N, Boxer AL. Progression of microstructural degeneration in progressive Supranuclear palsy and Corticobasal syndrome: a longitudinal diffusion tensor imaging study. PLoS One. 2016;11:e0157218.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

Supported by NIH grants (AG044372 and NS082730), the BrightFocus Foundation, the Secchia Family Foundation and the Rainwater Foundation.

Author information

Authors and Affiliations

  1. Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA

    Benjamin Combs, Rebecca L. Mueller & Nicholas M. Kanaan

  2. Neuroscience Program, Michigan State University, East Lansing, MI, USA

    Rebecca L. Mueller & Nicholas M. Kanaan

  3. Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA

    Gerardo Morfini & Scott T. Brady

  4. Marine Biological Laboratory, Woods Hole, MA, USA

    Gerardo Morfini & Scott T. Brady

  5. Hauenstein Neuroscience Center, Mercy Health Saint Mary’s, Grand Rapids, MI, USA

    Nicholas M. Kanaan

Authors
  1. Benjamin Combs
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rebecca L. Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gerardo Morfini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Scott T. Brady
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nicholas M. Kanaan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicholas M. Kanaan .

Editor information

Editors and Affiliations

  1. Department of Life Sciences, Gakushuin University, Tokyo, Japan

    Akihiko Takashima

  2. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA

    Benjamin Wolozin

  3. University of Lille, INSERM, CHU-Lille, Alzheimer & Tauopathies, LabEx DISTALZ, Lille, France

    Luc Buee

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Combs, B., Mueller, R.L., Morfini, G., Brady, S.T., Kanaan, N.M. (2019). Tau and Axonal Transport Misregulation in Tauopathies. In: Takashima, A., Wolozin, B., Buee, L. (eds) Tau Biology. Advances in Experimental Medicine and Biology, vol 1184. Springer, Singapore. https://doi.org/10.1007/978-981-32-9358-8_7

Download citation

Publish with us

Policies and ethics

Search

Navigation