Table of Contents Author Guidelines Submit a Manuscript
International Journal of Alzheimer’s Disease
Volume 2012 (2012), Article ID 172837, 16 pages
http://dx.doi.org/10.1155/2012/172837
Research Article

Accumulation of Vesicle-Associated Human Tau in Distal Dendrites Drives Degeneration and Tau Secretion in an In Situ Cellular Tauopathy Model

Department of Biological Sciences, Center for Cellular Neuroscience and Neurodegeneration Research, University of Massachusetts Lowell, Lowell, MA 01854, USA

Received 15 June 2011; Accepted 15 September 2011

Academic Editor: Vincenzo Solfrizzi

Copyright © 2012 Sangmook Lee et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. K. Iqbal, I. Grundke-Iqbal, T. Zaidi et al., “Defective brain microtubule assembly in Alzheimer's disease,” The Lancet, vol. 2, no. 8504, pp. 421–426, 1986. View at Google Scholar · View at Scopus
  2. A. C. Mckee, N. W. Kowall, and K. S. Kosik, “Microtubular reorganization and dendritic growth response in Alzheimer's disease,” Annals of Neurology, vol. 26, no. 5, pp. 652–659, 1989. View at Google Scholar · View at Scopus
  3. A. D. C. Alonso, T. Zaidi, M. Novak, I. Grundke-Iqbal, and K. Iqbal, “Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 12, pp. 6923–6928, 2001. View at Publisher · View at Google Scholar · View at Scopus
  4. J. Avila, “Tau phosphorylation and aggregation in Alzheimer's disease pathology,” FEBS Letters, vol. 580, no. 12, pp. 2922–2927, 2006. View at Publisher · View at Google Scholar · View at Scopus
  5. V. M. Y. Lee, M. Goedert, and J. Q. Trojanowski, “Neurodegenerative tauopathies,” Annual Review of Neuroscience, vol. 24, pp. 1121–1159, 2001. View at Publisher · View at Google Scholar · View at Scopus
  6. R. A. Crowther, O. F. Olesen, R. Jakes, and M. Goedert, “The microtubule binding repeats of tau protein assemble into filaments like those found in Alzheimer's disease,” FEBS Letters, vol. 309, no. 2, pp. 199–202, 1992. View at Publisher · View at Google Scholar · View at Scopus
  7. J. Götz, F. Chen, R. Barmettler, and R. M. Nitsch, “Tau filament formation in transgenic mice expressing P301L tau,” Journal of Biological Chemistry, vol. 276, no. 1, pp. 529–534, 2001. View at Publisher · View at Google Scholar · View at Scopus
  8. G. F. Hall, B. Chu, G. Lee, and J. Yao, “Human tau filaments induce microtubule and synapse loss in an in vivo model of neurofibrillary degenerative disease,” Journal of Cell Science, vol. 113, no. 8, pp. 1373–1387, 2000. View at Google Scholar · View at Scopus
  9. G. F. Hall, J. Yao, and G. Lee, “Human tau becomes phosphorylated and forms filamentous deposits when overexpressed in lamprey central neurons in situ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4733–4738, 1997. View at Publisher · View at Google Scholar · View at Scopus
  10. T. Ishihara, M. Hong, B. Zhang et al., “Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform,” Neuron, vol. 24, no. 3, pp. 751–762, 1999. View at Google Scholar · View at Scopus
  11. J. Lewis, E. McGowan, J. Rockwood et al., “Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein,” Nature Genetics, vol. 25, no. 4, pp. 402–405, 2000. View at Publisher · View at Google Scholar · View at Scopus
  12. C. W. Wittmann, M. F. Wszolek, J. M. Shulman et al., “Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles,” Science, vol. 293, no. 5530, pp. 711–714, 2001. View at Google Scholar · View at Scopus
  13. W. H. Stoothoff and G. V. W. Johnson, “Tau phosphorylation: physiological and pathological consequences,” Biochimica et Biophysica Acta, vol. 1739, no. 2, pp. 280–297, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Hasegawa, M. J. Smith, and M. Goedert, “Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly,” FEBS Letters, vol. 437, no. 3, pp. 207–210, 1998. View at Publisher · View at Google Scholar · View at Scopus
  15. M. Hong, V. Zhukareva, V. Vogelsberg-Ragaglia et al., “Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17,” Science, vol. 282, no. 5395, pp. 1914–1917, 1998. View at Google Scholar · View at Scopus
  16. P. Nacharaju, J. Lewis, C. Easson et al., “Accelerated filament formation from tau protein with specific FTDP-17 missense mutations,” FEBS Letters, vol. 447, no. 2-3, pp. 195–199, 1999. View at Publisher · View at Google Scholar · View at Scopus
  17. N. Sahara, T. Tomiyama, and H. Mori, “Missense point mutations of tau to segregate with FTDP-17 exhibit site-specific effects on microtubule structure in COS cells: a novel action of R406W mutation,” Journal of Neuroscience Research, vol. 60, no. 3, pp. 380–387, 2000. View at Publisher · View at Google Scholar · View at Scopus
  18. S. Lee, C. Jung, G. Lee, and G. F. Hall, “Exonic point mutations of human tau enhance its toxicity and cause characteristic changes in neuronal morphology, tau distribution and tau phosphorylation in the lamprey cellular model of tauopathy,” Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 99–111, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. M. Goedert and R. Jakes, “Mutations causing neurodegenerative tauopathies,” Biochimica et Biophysica Acta, vol. 1739, no. 2, pp. 240–250, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. M. G. Spillantini and M. Goedert, “Tau protein pathology in neurodegenerative diseases,” Trends in Neurosciences, vol. 21, no. 10, pp. 428–433, 1998. View at Publisher · View at Google Scholar · View at Scopus
  21. N. J. Cairns, V. M. Y. Lee, and J. Q. Trojanowski, “The cytoskeleton in neurodegenerative diseases,” Journal of Pathology, vol. 204, no. 4, pp. 438–449, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. A. L. Guillozet-Bongaarts, F. Garcia-Sierra, M. R. Reynolds et al., “Tau truncation during neurofibrillary tangle evolution in Alzheimer's disease,” Neurobiology of Aging, vol. 26, no. 7, pp. 1015–1022, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. M. M. Mocanu, A. Nissen, K. Eckermann et al., “The potential for β-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,” Journal of Neuroscience, vol. 28, no. 3, pp. 737–748, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. H. Yin and J. Kuret, “C-terminal truncation modulates both nucleation and extension phases of τ fibrillization,” FEBS Letters, vol. 580, no. 1, pp. 211–215, 2006. View at Publisher · View at Google Scholar · View at Scopus
  25. N. Zilka, P. Filipcik, P. Koson et al., “Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo,” FEBS Letters, vol. 580, no. 15, pp. 3582–3588, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. S. Maeda, N. Sahara, Y. Saito et al., “Granular tau oligomers as intermediates of tau filaments,” Biochemistry, vol. 46, no. 12, pp. 3856–3861, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. R. Brandt, J. Léger, and G. Lee, “Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain,” Journal of Cell Biology, vol. 131, no. 5, pp. 1327–1340, 1995. View at Publisher · View at Google Scholar · View at Scopus
  28. T. C. Gamblin, R. W. Berry, and L. I. Binder, “Tau polymerization: role of the amino terminus,” Biochemistry, vol. 42, no. 7, pp. 2252–2257, 2003. View at Publisher · View at Google Scholar · View at Scopus
  29. P. M. Horowitz, N. LaPointe, A. L. Guillozet-Bongaarts, R. W. Berry, and L. I. Binder, “N-terminal fragments of tau inhibit full-length tau polymerization in vitro,” Biochemistry, vol. 45, no. 42, pp. 12859–12866, 2006. View at Publisher · View at Google Scholar · View at Scopus
  30. G. S. Bloom, K. Ren, and C. G. Glabe, “Cultured cell and transgenic mouse models for tau pathology linked to β-amyloid,” Biochimica et Biophysica Acta, vol. 1739, no. 2, pp. 116–124, 2005. View at Publisher · View at Google Scholar
  31. M. E. King, H. M. Kan, P. W. Baas, A. Erisir, C. G. Glabe, and G. S. Bloom, “Tau-dependent microtubule disassembly initiated by prefibrillar β-amyloid,” Journal of Cell Biology, vol. 175, no. 4, pp. 541–546, 2006. View at Publisher · View at Google Scholar · View at Scopus
  32. G. Amadoro, A. L. Serafino, C. Barbato et al., “Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons,” Cell Death and Differentiation, vol. 11, no. 2, pp. 217–230, 2004. View at Publisher · View at Google Scholar · View at Scopus
  33. S. Y. Park and A. Ferreira, “The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates β-amyloid-induced neurodegeneration,” Journal of Neuroscience, vol. 25, no. 22, pp. 5365–5375, 2005. View at Publisher · View at Google Scholar · View at Scopus
  34. V. Corsetti, G. Amadoro, A. Gentile et al., “Identification of a caspase-derived N-terminal tau fragment in cellular and animal Alzheimer's disease models,” Molecular and Cellular Neuroscience, vol. 38, no. 3, pp. 381–392, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. K. Bhaskar, S. H. Yen, and G. Lee, “Disease-related modifications in tau affect the interaction between fyn and tau,” Journal of Biological Chemistry, vol. 280, no. 42, pp. 35119–35125, 2005. View at Publisher · View at Google Scholar · View at Scopus
  36. G. Lee, S. Todd Newman, D. L. Gard, H. Band, and G. Panchamoorthy, “Tau interacts with src-family non-receptor tyrosine kinases,” Journal of Cell Science, vol. 111, no. 21, pp. 3167–3177, 1998. View at Google Scholar · View at Scopus
  37. I. E. Vega, L. Cui, J. A. Propst, M. L. Hutton, G. Lee, and S. H. Yen, “Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates,” Molecular Brain Research, vol. 138, no. 2, pp. 135–144, 2005. View at Publisher · View at Google Scholar · View at Scopus
  38. T. A. Fulga, I. Elson-Schwab, V. Khurana et al., “Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo,” Nature Cell Biology, vol. 9, no. 2, pp. 139–148, 2007. View at Publisher · View at Google Scholar · View at Scopus
  39. C. A. Farah, S. Perreault, D. Liazoghli et al., “Tau interacts with golgi membranes and mediates their association with microtubules,” Cell Motility and the Cytoskeleton, vol. 63, no. 11, pp. 710–724, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. W. Kim, S. Lee, and G. F. Hall, “Secretion of human tau fragments resembling CSF-tau in Alzheimer's disease is modulated by the presence of the exon 2 insert,” FEBS Letters, vol. 584, no. 14, pp. 3085–3088, 2010. View at Publisher · View at Google Scholar · View at Scopus
  41. W. Kim, S. Lee, C. Jung, A. Ahmed, G. Lee, and G. F. Hall, “Interneuronal transfer of human tau between lamprey central neurons in situ,” Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 647–664, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. B. Frost, R. L. Jacks, and M. I. Diamond, “Propagation of tau misfolding from the outside to the inside of a cell,” Journal of Biological Chemistry, vol. 284, no. 19, pp. 12845–12852, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. F. Clavaguera, T. Bolmont, R. A. Crowther et al., “Transmission and spreading of tauopathy in transgenic mouse brain,” Nature Cell Biology, vol. 11, no. 7, pp. 909–913, 2009. View at Publisher · View at Google Scholar · View at Scopus
  44. S. J. Pleasure, M. E. Selzer, and V. M. Y. Lee, “Lamprey neurofilaments combine in one subunit the features of each mammalian NF triplet protein but are highly phosphorylated only in large axons,” Journal of Neuroscience, vol. 9, no. 2, pp. 698–709, 1989. View at Google Scholar · View at Scopus
  45. G. F. Hall, B. Chu, S. Lee, Y. Liu, and J. Yao, “The single neurofilament subunit of the lamprey forms filaments and regulates axonal caliber and neuronal size in vivo,” Cell Motility and the Cytoskeleton, vol. 46, no. 3, pp. 166–182, 2000. View at Publisher · View at Google Scholar · View at Scopus
  46. G. F. Hall, A. Poulos, and M. J. Cohen, “Sprouts emerging from the dendrites of axotomized Lamprey central neurons have axonlike ultrastructure,” Journal of Neuroscience, vol. 9, no. 2, pp. 588–599, 1989. View at Google Scholar · View at Scopus
  47. G. F. Hall, V. M. Y. Lee, and K. S. Kosik, “Microtubule destabilization and neurofilament phosphorylation precede dendritic sprouting after close axotomy of lamprey central neurons,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 11, pp. 5016–5020, 1991. View at Google Scholar · View at Scopus
  48. G. F. Hall, J. Yao, M. E. Selzer, and K. S. Kosik, “Cytoskeletal changes correlated with the loss of neuronal polarity in axotomized lamprey central neurons,” Journal of Neurocytology, vol. 26, no. 11, pp. 733–753, 1997. View at Publisher · View at Google Scholar · View at Scopus
  49. G. F. Hall and V. M. Y. Lee, “Neurofilament sidearm proteolysis is a prominent early effect of axotomy in lamprey giant central neurons,” Journal of Comparative Neurology, vol. 353, no. 1, pp. 38–49, 1995. View at Publisher · View at Google Scholar · View at Scopus
  50. D. S. Pijak, G. F. Hall, P. J. Tenicki, A. S. Boulos, D. I. Lurie, and M. E. Selzer, “Neurofilament spacing, phosphorylation, and axon diameter in regenerating and uninjured lamprey axons,” Journal of Comparative Neurology, vol. 368, no. 4, pp. 569–581, 1996. View at Google Scholar · View at Scopus
  51. M. Goedert, C. P. Baur, J. Ahringer et al., “PTL-1, a microtubule-associated protein with tau-like repeats from the nematode Caenorhabditis elegans,” Journal of Cell Science, vol. 109, no. 11, pp. 2661–2672, 1996. View at Google Scholar · View at Scopus
  52. G. F. Hall, V. M. Y. Lee, G. Lee, and J. Yao, “Staging of neurofibrillary degeneration caused by human tau overexpression in a unique cellular model of human tauopathy,” American Journal of Pathology, vol. 158, no. 1, pp. 235–246, 2001. View at Google Scholar · View at Scopus
  53. A. Schneider, J. Biernat, M. Von Bergen, E. Mandelkow, and E. M. Mandelkow, “Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments,” Biochemistry, vol. 38, no. 12, pp. 3549–3558, 1999. View at Publisher · View at Google Scholar · View at Scopus
  54. D. Fischer, M. D. Mukrasch, J. Biernat et al., “Conformational changes specific for pseudophosphorylation at serine 262 selectively impair binding of tau to microtubules,” Biochemistry, vol. 48, no. 42, pp. 10047–10055, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. P. Seubert, M. Mawal-Dewan, R. Barbour et al., “Detection of phosphorylated Ser262 in fetal tau, adult tau, and paired helical filament tau,” Journal of Biological Chemistry, vol. 270, no. 32, pp. 18917–18922, 1995. View at Publisher · View at Google Scholar · View at Scopus
  56. H. Kameda, T. Furuta, W. Matsuda et al., “Targeting green fluorescent protein to dendritic membrane in central neurons,” Neuroscience Research, vol. 61, no. 1, pp. 79–91, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. J. B. McCabe and L. G. Berthiaume, “Functional roles for fatty acylated amino-terminal domains in subcellular localization,” Molecular Biology of the Cell, vol. 10, no. 11, pp. 3771–3786, 1999. View at Google Scholar · View at Scopus
  58. J.-P. Brion, G. Tremp, and J.-N. Octave, “Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer's disease,” American Journal of Pathology, vol. 154, no. 1, pp. 255–270, 1999. View at Google Scholar
  59. J. Gotz, A. Probst, M. G. Spillantini et al., “Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform,” The EMBO Journal, vol. 14, no. 7, pp. 1304–1313, 1995. View at Google Scholar · View at Scopus
  60. Y. Kanai and N. Hirokawa, “Sorting mechanisms of tau and MAP2 in neurons: suppressed axonal transit of MAP2 and locally regulated microtubule binding,” Neuron, vol. 14, no. 2, pp. 421–432, 1995. View at Google Scholar · View at Scopus
  61. P. Litman, J. Barg, L. Rindzoonski, and I. Ginzburg, “Subcellular localization of tau mRNA in differentiating neuronal cell culture: implications for neuronal polarity,” Neuron, vol. 10, no. 4, pp. 627–638, 1993. View at Publisher · View at Google Scholar · View at Scopus
  62. A. J. Myers, A. M. Pittman, A. S. Zhao et al., “The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts,” Neurobiology of Disease, vol. 25, no. 3, pp. 561–570, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. A. Samsonov, J. Z. Yu, M. Rasenick, and S. V. Popov, “Tau interaction with microtubules in vivo,” Journal of Cell Science, vol. 117, no. 25, pp. 6129–6141, 2004. View at Publisher · View at Google Scholar · View at Scopus
  64. R. Dixit, J. L. Ross, Y. E. Goldman, and E. L. F. Holzbaur, “Differential regulation of dynein and kinesin motor proteins by tau,” Science, vol. 319, no. 5866, pp. 1086–1089, 2008. View at Publisher · View at Google Scholar · View at Scopus
  65. L. C. Kapitein, M. A. Schlager, M. Kuijpers et al., “Mixed microtubules steer dynein-driven cargo transport into dendrites,” Current Biology, vol. 20, no. 4, pp. 290–299, 2010. View at Publisher · View at Google Scholar · View at Scopus
  66. L. M. Ittner, Y. D. Ke, and J. Götz, “Phosphorylated tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease,” Journal of Biological Chemistry, vol. 284, no. 31, pp. 20909–20916, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. T. L. Falzone, G. B. Stokin, C. Lillo et al., “Axonal stress kinase activation and tau misbehavior induced by kinesin-1 transport defects,” Journal of Neuroscience, vol. 29, no. 18, pp. 5758–5767, 2009. View at Publisher · View at Google Scholar · View at Scopus
  68. E. Braak, H. Braaak, and E. M. Mandelkow, “A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads,” Acta Neuropathologica, vol. 87, no. 6, pp. 554–567, 1994. View at Publisher · View at Google Scholar · View at Scopus
  69. C. Bancher, C. Brunner, H. Lassmann et al., “Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer's disease,” Brain Research, vol. 477, no. 1-2, pp. 90–99, 1989. View at Google Scholar · View at Scopus
  70. N. Sahara, S. Maeda, and A. Takashima, “Tau oligomerization: a role for tau aggregation intermediates linked to neurodegeneration,” Current Alzheimer Research, vol. 5, no. 6, pp. 591–598, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. K. Santacruz, J. Lewis, T. Spires et al., “Medicine: tau suppression in a neurodegenerative mouse model improves memory function,” Science, vol. 309, no. 5733, pp. 476–481, 2005. View at Publisher · View at Google Scholar · View at Scopus
  72. C. N. Chirita, M. Necula, and J. Kuret, “Anionic micelles and vesicles induce tau fibrillization in vitro,” Journal of Biological Chemistry, vol. 278, no. 28, pp. 25644–25650, 2003. View at Publisher · View at Google Scholar · View at Scopus
  73. P. Barré and D. Eliezer, “Folding of the repeat domain of tau upon binding to lipid surfaces,” Journal of Molecular Biology, vol. 362, no. 2, pp. 312–326, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. E. G. Gray, M. Paula-Barbosa, and A. Roher, “Alzheimer's disease: paired helical filaments and cytomembranes,” Neuropathology and Applied Neurobiology, vol. 13, no. 2, pp. 91–110, 1987. View at Google Scholar · View at Scopus
  75. I. Grundke-Iqbal, K. Iqbal, and Y.-C. Tung, “Abnormal phosphorylation of the microtubule-associated protein τ (tau) in Alzheimer cytoskeletal pathology,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 13, pp. 4913–4917, 1986. View at Google Scholar
  76. A. M. Cataldo, D. J. Hamilton, and R. A. Nixon, “Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer disease,” Brain Research, vol. 640, no. 1-2, pp. 68–80, 1994. View at Google Scholar · View at Scopus
  77. T. Hamano, T. F. Gendron, E. Causevic et al., “Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression,” European Journal of Neuroscience, vol. 27, no. 5, pp. 1119–1130, 2008. View at Publisher · View at Google Scholar · View at Scopus
  78. V. Khurana, I. Elson-Schwab, T. A. Fulga et al., “Lysosomal dysfunction promotes cleavage and neurotoxicity of tau in vivo,” PLoS Genetics, vol. 6, no. 7, Article ID e1001026, 11 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. B. Boland, A. Kumar, S. Lee et al., “Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease,” Journal of Neuroscience, vol. 28, no. 27, pp. 6926–6937, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. P. J. Dolan and G. V. W. Johnson, “A caspase cleaved form of tau is preferentially degraded through the autophagy pathway,” Journal of Biological Chemistry, vol. 285, no. 29, pp. 21978–21987, 2010. View at Publisher · View at Google Scholar · View at Scopus
  81. R. A. Nixon, J. Wegiel, A. Kumar et al., “Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study,” Journal of Neuropathology and Experimental Neurology, vol. 64, no. 2, pp. 113–122, 2005. View at Google Scholar · View at Scopus
  82. S. Saman, W. Kim, M. Raya et al., “Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid (CSF) in early Alzheimer's Disease,” The Journal of Biological Chemistry. In press.
  83. M. P. Lambert, A. K. Barlow, B. A. Chromy et al., “Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 11, pp. 6448–6453, 1998. View at Google Scholar · View at Scopus
  84. M. Rapoport, H. N. Dawson, L. I. Binder, M. P. Vitek, and A. Ferreira, “Tau is essential to β-amyloid-induced neurotoxicity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 9, pp. 6364–6369, 2002. View at Publisher · View at Google Scholar · View at Scopus
  85. G. Lee, R. Thangavel, V. M. Sharma et al., “Phosphorylation of tau by fyn: implications for Alzheimer's disease,” Journal of Neuroscience, vol. 24, no. 9, pp. 2304–2312, 2004. View at Publisher · View at Google Scholar · View at Scopus
  86. G. J. Ho, M. Hashimoto, A. Adame et al., “Altered p59Fyn kinase expression accompanies disease progression in Alzheimer's disease: implications for its functional role,” Neurobiology of Aging, vol. 26, no. 5, pp. 625–635, 2005. View at Publisher · View at Google Scholar · View at Scopus
  87. N. Blanchard, D. Lankar, F. Faure et al., “TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/ζ complex,” Journal of Immunology, vol. 168, no. 7, pp. 3235–3241, 2002. View at Google Scholar · View at Scopus
  88. M. Sverdlov, A. N. Shajahan, and R. D. Minshall, “Tyrosine phosphorylation-dependence of caveolae-mediated endocytosis,” Journal of Cellular and Molecular Medicine, vol. 11, no. 6, pp. 1239–1250, 2007. View at Publisher · View at Google Scholar · View at Scopus
  89. Y. Fang, N. Wu, X. Gan, W. Yan, J. C. Morrell, and S. J. Gould, “Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes,” PLoS Biology, vol. 5, no. 6, article e158, 2007. View at Publisher · View at Google Scholar · View at Scopus
  90. W. Nickel, “Unconventional secretory routes: direct protein export across the plasma membrane of mammalian cells,” Traffic, vol. 6, no. 8, pp. 607–614, 2005. View at Publisher · View at Google Scholar · View at Scopus
  91. Y. Wang, M. Martinez-Vicente, U. Krüger et al., “Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing,” Human Molecular Genetics, vol. 18, no. 21, pp. 4153–4170, 2009. View at Publisher · View at Google Scholar · View at Scopus
  92. O. T. Fackler and R. Grosse, “Cell motility through plasma membrane blebbing,” Journal of Cell Biology, vol. 181, no. 6, pp. 879–884, 2008. View at Publisher · View at Google Scholar · View at Scopus
  93. L. M. Ittner, Y. D. Ke, F. Delerue et al., “Dendritic function of tau mediates amyloid-β toxicity in alzheimer's disease mouse models,” Cell, vol. 142, no. 3, pp. 387–397, 2010. View at Publisher · View at Google Scholar · View at Scopus