Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress
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We studied the effect of microtubule-associated tau protein on trafficking of vesicles and organelles in primary cortical neurons, retinal ganglion cells, and neuroblastoma cells. Tau inhibits kinesin-dependent transport of peroxisomes, neurofilaments, and Golgi-derived vesicles into neurites. Loss of peroxisomes makes cells vulnerable to oxidative stress and leads to degeneration. In particular, tau inhibits transport of amyloid precursor protein (APP) into axons and dendrites, causing its accumulation in the cell body. APP tagged with yellow fluorescent protein and transfected by adenovirus associates with vesicles moving rapidly forward in the axon (∼80%) and slowly back (∼20%). Both movements are strongly inhibited by cotransfection with fluorescently tagged tau (cyan fluorescent protein–tau) as seen by two-color confocal microscopy. The data suggests a linkage between tau and APP trafficking, which may be significant in Alzheimer's disease.
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Neurofibrillary tangles appear to be toxic since they are associated with impaired axonal transport, which provokes cell death.
“However, neurofibrillary tangles appear to be toxic since they are associated with impaired axonal transport, which provokes cell death (Stamer et al., 2002; Terwel et al., 2002; Cente et al., 2006; Smith et al., 2007).”
From The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease (2013) · cites this paper as Stamer et al., 2002
The Discussion (page not provided) links elevated tau to impaired intracellular transport and suggests that resulting traffic jams may speed degeneration. It does not show that neurofibrillary tangles cause the transport defect or that the defect provokes cell death; it notes transport defects even when tau aggregates are absent or minor. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOverexpression of Tau in CHO cells and N2a neuroblastoma cells inhibits kinesin-dependent trafficking of vesicles and disturbs the organization of intermediate filaments.
“In contrast, other reports on Chinese hamster ovary (CHO) cells [21, 22] and N2a neuroblastoma cells [23] concluded that overexpression of Tau inhibits kinesin-dependent trafficking of vesicles and disturbs the organization of intermediate filaments.”
From Expression of Tau Produces Aberrant Plasma Membrane Blebbing in Glial Cells Through RhoA-ROCK-Dependent F-Actin Remodeling (2016) · cites this paper as [23]
Overexpression of Tau inhibits mitochondrial transport in various cells.
“Overexpression of Tau inhibits mitochondrial transport in various cells (Ebneth et al., 1998;Trinczek et al., 1999;Stamer et al., 2002;Dixit et al., 2008;Stoothoff et al., 2009;Vossel et al., 2010).”
From Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease (2012) · cites this paper as Stamer et al., 2002
Tau WT overexpression increased the pausing frequency from 31.6 to 48.5% in neurons.
“Tau WT overexpression increased the pausing frequency from 31.6 to 48.5% in neurons, which is almost identical to previous results (Stamer et al., 2002).”
From Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease (2012) · cites this paper as Stamer et al., 2002
Tau overexpression inhibits mitochondrial movement in various cell types.
“Tau overexpression inhibits mitochondrial movement in various cell types (Ebneth et al., 1998;Trinczek et al., 1999;Stamer et al., 2002;Dixit et al., 2008;Stoothoff et al., 2009;Vossel et al., 2010).”
From Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease (2012) · cites this paper as Stamer et al., 2002
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Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T., & Hyman, B. T. (1992) · Neurology · doi:10.1212/wnl.42.3.631 · Cited by 2,668 · see citing works
A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60
Cao, X., & Südhof, T. C. (2001) · Science · doi:10.1126/science.1058783 · Cited by 1,202 · see citing works
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Research works printed but not linked: 67
- Amaratunga, A., and R.E. Fine. 1995. Generation of amyloidogenic C-terminal fragments during rapid axonal transport in vivo of beta-amyloid precursor protein in the optic nerve. J. Biol. Chem. 270: 17268–17272. 7542234
- Amaratunga, A., S.E. Leeman, K.S. Kosik, and R.E. Fine. 1995. Inhibition of kinesin synthesis in vivo inhibits the rapid transport of representative proteins for three transport vesicle classes into the axon. J. Neurochem. 64: 2374–2376. 7536813
- Baas, P.W. 1999. Microtubules and neuronal polarity: lessons from mitosis. Neuron. 22: 23–31. 10027286
- Banker, G.A., and K. Goslin. 1998. Culturing Nerve Cells. MIT Press, Cambridge, Massachusetts. 666 pp.
- Binder, L.I., A. Frankfurter, and L.I. Rebhun. 1985. The distribution of tau in the mammalian central nervous system. J. Cell Biol. 101: 1371–1378. 3930508 PMC2113928
- Bradke, F., and C.G. Dotti. 1998. Membrane traffic in polarized neurons. Biochim. Biophys. Acta. 1404: 245–258. 9714822
- Brandt, R., J. Leger, and G. Lee. 1995. Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain. J. Cell Biol. 131: 1327–1340. 8522593 PMC2120645
- Buee, L., T. Bussiere, V. Buee-Scherrer, A. Delacourte, and P.R. Hof. 2000. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res. Brain Res. Rev. 33: 95–130. 10967355
- Bulinski, J.C., T.E. McGraw, D. Gruber, H.L. Nguyen, and M.P. Sheetz. 1997. Overexpression of MAP4 inhibits organelle motility and trafficking in vivo. J. Cell Sci. 110: 3055–3064. 9365275
- Caceres, A., and K.S. Kosik. 1990. Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons. Nature. 343: 461–463. 2105469
- Chou, Y.H., B.T. Helfand, and R.D. Goldman. 2001. New horizons in cytoskeletal dynamics: transport of intermediate filaments along microtubule tracks. Curr. Opin. Cell Biol. 13: 106–109. 11163141
- Cleveland, D.W., S.Y. Hwo, and M.W. Kirschner. 1977. Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J. Mol. Biol. 116: 227–247. 146092
- Dringen, R., L. Kussmaul, J.M. Gutterer, J. Hirrlinger, and B. Hamprecht. 1999. The glutathione system of peroxide detoxification is less efficient in neurons than in astroglial cells. J. Neurochem. 72: 2523–2530. 10349863
- Drubin, D.G., and M.W. Kirschner. 1986. Tau protein function in living cells. J. Cell Biol. 103: 2739–2746. 3098742 PMC2114585
- Ebneth, A., R. Godemann, K. Stamer, S. Illenberger, B. Trinczek, and E. Mandelkow. 1998. Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. J. Cell Biol. 143: 777–794. 9813097 PMC2148132
- Ellenberg, J., J. Lippincott-Schwartz, and J.F. Presley. 1999. Dual-colour imaging with GFP variants. Trends Cell Biol. 9: 52–56. 10087618
- Ferreira, A., A. Caceres, and K.S. Kosik. 1993. Intraneuronal compartments of the amyloid precursor protein. J. Neurosci. 13: 3112–3123. 8331388 PMC6576677
- Garcia, M.L., and D.W. Cleveland. 2001. Going new places using an old MAP: tau, microtubules and human neurodegenerative disease. Curr. Opin. Cell Biol. 13: 41–48. 11163132
- Goldstein, L.S. 2001. Kinesin molecular motors: transport pathways, receptors, and human disease. Proc. Natl. Acad. Sci. USA. 98: 6999–7003. 11416178 PMC34613
- Gonatas, N.K., and S. Avrameas. 1977. Detection of carbohydrates with lectin-peroxidase conjugates. Methods Cell Biol. 15: 387–406. 327205
- Götz, J., F. Chen, J. van Dorpe, and R.M. Nitsch. 2001. Formation of neurofibrillary tangles in P301L tau transgenic mice induced by AB42 fibrils. Science. 293: 1491–1495. 11520988
- Greenfield, J.P., J. Tsai, G.K. Gouras, B. Hai, G. Thinakaran, F. Checler, S.S. Sisodia, P. Greengard, and H. Xu. 1999. Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides. Proc. Natl. Acad. Sci. USA. 96: 742–747. 9892704 PMC15207
- Gundersen, G.G., and T.A. Cook. 1999. Microtubules and signal transduction. Curr. Opin. Cell Biol. 11: 81–94. 10047525
- Harada, A., K. Oguchi, S. Okabe, J. Kuno, S. Terada, T. Ohshima, R. Sato-Yoshitake, Y. Takei, T. Noda, and N. Hirokawa. 1994. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature. 369: 488–491. 8202139
- He, T.C., S. Zhou, L.T. da Costa, J. Yu, K.W. Kinzler, and B. Vogelstein. 1998. A simplified system for generating recombinant adenoviruses. Proc. Natl. Acad. Sci. USA. 95: 2509–2514. 9482916 PMC19394
- Hirokawa, N., Y. Noda, and Y. Okada. 1998. Kinesin and dynein superfamily proteins in organelle transport and cell division. Curr. Opin. Cell Biol. 10: 60–73. 9484596
- Hutton, M. 2001. Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurology. 56: S21–S25. 11402146
- Ishihara, T., M. Hong, B. Zhang, Y. Nakagawa, M.K. Lee, J.Q. Trojanowski, and V.M. Lee. 1999. Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron. 24: 751–762. 10595524
- Ishihara, T., M. Higuchi, B. Zhang, Y. Yoshiyama, M. Hong, J.Q. Trojanowski, and V.M. Lee. 2001. Attenuated neurodegenerative disease phenotype in tau transgenic mouse lacking neurofilaments. J. Neurosci. 21: 6026–6035. 11487626 PMC6763173
- Kaether, C., P. Skehel, and C.G. Dotti. 2000. Axonal membrane proteins are transported in distinct carriers: a two-color video microscopy study in cultured hippocampal neurons. Mol. Biol. Cell. 11: 1213–1224. 10749925 PMC14842
- Kamal, A., G.B. Stokin, Z. Yang, C.H. Xia, and L.S. Goldstein. 2000. Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron. 28: 449–459. 11144355
- Khatoon, S., I. Grundke-Iqbal, and K. Iqbal. 1992. Brain levels of microtubule-associated protein tau are elevated in Alzheimer's disease: a radioimmuno-slot-blot assay for nanograms of the protein. J. Neurochem. 59: 750–753. 1629745
- Kopito, R.R. 2000. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 10: 524–530. 11121744
- Lee, G., S.T. Newman, D.L. Gard, H. Band, and G. Panchamoorthy. 1998. Tau interacts with src-family non-receptor tyrosine kinases. J. Cell Sci. 111: 3167–3177. 9763511
- Lewis, J., D.W. Dickson, W.L. Lin, L. Chisholm, A. Corral, G. Jones, S.H. Yen, N. Sahara, L. Skipper, D. Yager, et al. 2001. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 293: 1487–1491. 11520987
- Liao, G., and G.G. Gundersen. 1998. Kinesin is a candidate for cross-bridging microtubules and intermediate filaments. Selective binding of kinesin to detyrosinated tubulin and vimentin. J. Biol. Chem. 273: 9797–9803. 9545318
- Liao, H., Y. Li, D.L. Brautigan, and G.G. Gundersen. 1998. Protein phosphatase 1 is targeted to microtubules by the microtubule-associated protein Tau. J. Biol. Chem. 273: 21901–21908. 9705329
- Lu, M., and K.S. Kosik. 2001. Competition for microtubule-binding with dual expression of tau missense and splice isoforms. Mol. Biol. Cell. 12: 171–184. 11160831 PMC30576
- Mandell, J.W., and G.A. Banker. 1996. A spatial gradient of tau protein phosphorylation in nascent axons. J. Neurosci. 16: 5727–5740. 8795628 PMC6578967
- Mattson, M.P., S.W. Barger, J.G. Begley, and R.J. Mark. 1995. Calcium, free radicals, and excitotoxic neuronal death in primary cell culture. Methods Cell Biol. 46: 187–216. 7541884
- Morin, P.J., C.R. Abraham, A. Amaratunga, R.J. Johnson, G. Huber, J.H. Sandell, and R.E. Fine. 1993. Amyloid precursor protein is synthesized by retinal ganglion cells, rapidly transported to the optic nerve plasma membrane and nerve terminals, and metabolized. J. Neurochem. 61: 464–473. 7687653
- Morris, R.L., and P.J. Hollenbeck. 1995. Axonal transport of mitochondria along microtubules and F-actin in living vertebrate neurons. J. Cell Biol. 131: 1315–1326. 8522592 PMC2120647
- Muchowski, P.J., G. Schaffar, A. Sittler, E.E. Wanker, M.K. Hayer-Hartl, and F.U. Hartl. 2000. Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl. Acad. Sci. USA. 97: 7841–7846. 10859365 PMC16632
- Preuss, U., J. Biernat, E.M. Mandelkow, and E. Mandelkow. 1997. The ‘jaws’ model of tau-microtubule interaction examined in CHO cells. J. Cell Sci. 110: 789–800. 9099953
- Price, D.L., S.S. Sisodia, and D.R. Borchelt. 1998. Genetic neurodegenerative diseases: the human illness and transgenic models. Science. 282: 1079–1083. 9804539
- Ratner, N., G.S. Bloom, and S.T. Brady. 1998. A role for cyclin-dependent kinase(s) in the modulation of fast anterograde axonal transport: effects defined by olomoucine and the APC tumor suppressor protein. J. Neurosci. 18: 7717–7726. 9742142 PMC6793030
- Riederer, B.M., and L.I. Binder. 1994. Differential distribution of tau proteins in developing cat cerebellum. Brain Res. Bull. 33: 155–161. 8275333
- Rogers, S.L., and V.I. Gelfand. 2000. Membrane trafficking, organelle transport, and the cytoskeleton. Curr. Opin. Cell Biol. 12: 57–62. 10679352
- Roy, S., P. Coffee, G. Smith, R.K. Liem, S.T. Brady, and M.M. Black. 2000. Neurofilaments are transported rapidly but intermittently in axons: implications for slow axonal transport. J. Neurosci. 20: 6849–6861. 10995829 PMC6772820
- Sato-Harada, R., S. Okabe, T. Umeyama, Y. Kanai, and N. Hirokawa. 1996. Microtubule-associated proteins regulate microtubule function as the track for intracellular membrane organelle transports. Cell Struct. Funct. 21: 283–295. 9118234
- Savaskan, N.E., and R. Nitsch. 2001. Molecules involved in reactive sprouting in the hippocampus. Rev. Neurosci. 12: 195–215. 11560368
- Setou, M., T. Nakagawa, D.H. Seog, and N. Hirokawa. 2000. Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science. 288: 1796–1802. 10846156
- Shea, T.B., and L.A. Flanagan. 2001. Kinesin, dynein and neurofilament transport. Trends Neurosci. 24: 644–648. 11672808
- Sheetz, M.P., K.K. Pfister, J.C. Bulinski, and C.W. Cotman. 1998. Mechanisms of trafficking in axons and dendrites: implications for development and neurodegeneration. Prog. Neurobiol. 55: 577–594. 9670219
- Simons, M., E. Ikonen, P.J. Tienari, A. Cid-Arregui, U. Monning, K. Beyreuther, and C.G. Dotti. 1995. Intracellular routing of human amyloid protein precursor: axonal delivery followed by transport to the dendrites. J. Neurosci. Res. 41: 121–128. 7674373
- Sontag, E., V. Nunbhakdi-Craig, G. Lee, R. Brandt, C. Kamibayashi, J. Kuret, C.L. White III, M.C. Mumby, and G.S. Bloom. 1999. Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies. J. Biol. Chem. 274: 25490–25498. 10464280
- Takei, Y., J. Teng, A. Harada, and N. Hirokawa. 2000. Defects in axonal elongation and neuronal migration in mice with disrupted tau and map1b genes. J. Cell Biol. 150: 989–1000. 10973990 PMC2175245
- Terry, R.D. 1998. The cytoskeleton in Alzheimer disease. J. Neural Transm. Suppl. 53: 141–145. 9700652
- Thinakaran, G., D.B. Teplow, R. Siman, B. Greenberg, and S.S. Sisodia. 1996. Metabolism of the “Swedish” amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the “beta-secretase” site occurs in the golgi apparatus. J. Biol. Chem. 271: 9390–9397. 8621605
- Trinczek, B., A. Ebneth, E.M. Mandelkow, and E. Mandelkow. 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: 2355–2367. 10381391
- Verhey, K.J., D. Meyer, R. Deehan, J. Blenis, B.J. Schnapp, T.A. Rapoport, and B. Margolis. 2001. Cargo of kinesin identified as JIP scaffolding proteins and associated signaling molecules. J. Cell Biol. 152: 959–970. 11238452 PMC2198804
- Walter, J., B. Kern-Veits, J. Huf, B. Stolze, and F. Bonhoeffer. 1987. Recognition of position-specific properties of tectal cell membranes by retinal axons in vitro. Development. 101: 685–696. 3503693
- Wang, L., C.L. Ho, D. Sun, R.K. Liem, and A. Brown. 2000. Rapid movement of axonal neurofilaments interrupted by prolonged pauses. Nat. Cell Biol. 2: 137–141. 10707083
- Wittmann, C.W., M.F. Wszolek, J.M. Shulman, P.M. Salvaterra, J. Lewis, M. Hutton, and M.B. Feany. 2001. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science. 293: 711–714. 11408621
- Xu, H., D. Sweeney, R. Wang, G. Thinakaran, A.C. Lo, S.S. Sisodia, P. Greengard, and S. Gandy. 1997. Generation of Alzheimer beta-amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation. Proc. Natl. Acad. Sci. USA. 94: 3748–3752. 9108049 PMC20512
- Yabe, J.T., A. Pimenta, and T.B. Shea. 1999. Kinesin-mediated transport of neurofilament protein oligomers in growing axons. J. Cell Sci. 112: 3799–3814. 10523515
- Zhou, H.M., I. Brust-Mascher, and J.M. Scholey. 2001. Direct visualization of the movement of the monomeric axonal transport motor UNC-104 along neuronal processes in living Caenorhabditis elegans. J. Neurosci. 21: 3749–3755. 11356862 PMC6762686
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Mudher, A., Shepherd, D., Newman, T. A., Mildren, P., Jukes, J. P., Squire, A., Mears, A., Berg, S., MacKay, D., Asuni, A. A., et al. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001483 · Cited by 265 · see citing works
Mitochondria and Calcium in Alzheimer’s Disease: From Cell Signaling to Neuronal Cell Death
Calvo-Rodriguez, M., & Bacskai, B. J. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2020.10.004 · Cited by 254 · see citing works
Single-molecule investigation of the interference between kinesin, tau and MAP2c
Seitz, A., Kojima, H., Oiwa, K., Mandelkow, E.-M., Song, Y.-H., & Mandelkow, E. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf503 · Cited by 257 · see citing works
Self-citationKinesin Assembly and Movement in Cells
Verhey, K. J., Kaul, N., & Soppina, V. (2011) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-042910-155310 · Cited by 231 · see citing works
Structural Principles of Tau and the Paired Helical Filaments of Alzheimer's Disease
Mandelkow, E., Von Bergen, M., Biernat, J., & Mandelkow, E. (2007) · Brain Pathology · doi:10.1111/j.1750-3639.2007.00053.x · Cited by 243 · see citing works
Self-citationPeroxisomal alterations in Alzheimer’s disease
Kou, J., Kovacs, G. G., Höftberger, R., Kulik, W., Brodde, A., Forss-Petter, S., Hönigschnabl, S., Gleiss, A., Brügger, B., Wanders, R., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0836-9 · Cited by 227 · see citing works
“Previous observations in cultured neurons demonstrated that overexpression of tau inhibits kinesin-dependent transport of peroxisomes in neurites [28, 38].”
BackgroundSoluble forms of tau are toxic in Alzheimer's disease
Kopeikina, K., Hyman, B., & Spires-Jones, T. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0032-y · Cited by 232 · see citing works
Mitochondrial Medicine for Aging and Neurodegenerative Diseases
Reddy, P. H. (2008) · NeuroMolecular Medicine · doi:10.1007/s12017-008-8044-z · Cited by 230 · see citing works
Shahpasand, K., Uemura, I., Saito, T., Asano, T., Hata, K., Shibata, K., Toyoshima, Y., Hasegawa, M., & Hisanaga, S.-I. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5927-11.2012 · Cited by 206 · see citing works
A role for tau at the synapse in Alzheimer’s disease pathogenesis
Pooler, A. M., Noble, W., & Hanger, D. P. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.09.018 · Cited by 203 · see citing works
Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease
Cioffi, F., Adam, R. H. I., & Broersen, K. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190863 · Cited by 204 · see citing works
“In another study, methionine 35 of synthesized A 1-42 was oxidized by exposure to H2O2 and oxidation was validated using mass spectrometry.”
BackgroundInfluentialThe Role of Caspase Cleavage of Tau in Alzheimer Disease Neuropathology
Cotman, C. W., Poon, W. W., Rissman, R. A., & Blurton-Jones, M. (2005) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/64.2.104 · Cited by 199 · see citing works
Pathological Tau Disrupts Ongoing Network Activity
Menkes-Caspi, N., Yamin, H. G., Kellner, V., Spires-Jones, T. L., Cohen, D., & Stern, E. A. (2015) · Neuron · doi:10.1016/j.neuron.2015.01.025 · Cited by 184 · see citing works
Eckert, A., Schmitt, K., & Götz, J. (2011) · Alzheimer's Research & Therapy · doi:10.1186/alzrt74 · Cited by 177 · see citing works
Molecular pathways that influence human tau-induced pathology in Caenorhabditis elegans
Kraemer, B. C., Burgess, J. K., Chen, J. H., Thomas, J. H., & Schellenberg, G. D. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl067 · Cited by 150 · see citing works
Spilsbury, A., Miwa, S., Attems, J., & Saretzki, G. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2925-14.2015 · Cited by 140 · see citing works
Differential effect of three‐repeat and four‐repeat tau on mitochondrial axonal transport
Stoothoff, W., Jones, P. B., Spires‐Jones, T. L., Joyner, D., Chhabra, E., Bercury, K., Fan, Z., Xie, H., Bacskai, B., Edd, J., et al. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06316.x · Cited by 135 · see citing works
Is Alzheimer’s a disease of the white matter?
Sachdev, P. S., Zhuang, L., Braidy, N., & Wen, W. (2013) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e32835ed6e8 · Cited by 137 · see citing works
Merino-Serrais, P., Benavides-Piccione, R., Blazquez-Llorca, L., Kastanauskaite, A., Rábano, A., Avila, J., & DeFelipe, J. (2013) · Brain · doi:10.1093/brain/awt088 · Cited by 134 · see citing works
Traffic at the intersection of neurotrophic factor signaling and neurodegeneration
Salehi, A., Delcroix, J.-D., & Mobley, W. C. (2003) · Trends in Neurosciences · doi:10.1016/s0166-2236(02)00038-3 · Cited by 131 · see citing works
Connecting the dots between tau dysfunction and neurodegeneration
Frost, B., Götz, J., & Feany, M. B. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.07.005 · Cited by 124 · see citing works
Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets
Lee, V. M.-Y., Brunden, K. R., Hutton, M., & Trojanowski, J. Q. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006437 · Cited by 122 · see citing works
Axonal degeneration as a therapeutic target in the CNS
Lingor, P., Koch, J. C., Tönges, L., & Bähr, M. (2012) · Cell and Tissue Research · doi:10.1007/s00441-012-1362-3 · Cited by 119 · see citing works
Ambegaokar, S. S., & Jackson, G. R. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr432 · Cited by 113 · see citing works
“Tau mediates interactions between microtubules and the GA to maintain structure of the latter (231), and tau may function in regulating transport of Golgi-derived endosomes and vesicular organelles such as peroxisomes and lysosomes (232,233).”
BackgroundBernardo, T. C., Marques‐Aleixo, I., Beleza, J., Oliveira, P. J., Ascensão, A., & Magalhães, J. (2016) · Brain Pathology · doi:10.1111/bpa.12403 · Cited by 108 · see citing works
Cleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment
Garg, S., Timm, T., Mandelkow, E.-M., Mandelkow, E., & Wang, Y. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.09.008 · Cited by 103 · see citing works
Self-citationAxonal degeneration in tauopathies: disease relevance and underlying mechanisms
Kneynsberg, A., Combs, B., Christensen, K., Morfini, G., & Kanaan, N. M. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00572 · Cited by 102 · see citing works
Scheff, S. W., Ansari, M. A., & Mufson, E. J. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.02.030 · Cited by 100 · see citing works
Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma
Inman, D. M., & Harun-Or-Rashid, M. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00146 · Cited by 88 · see citing works
Inhibition of APP Trafficking by Tau Protein Does Not Increase the Generation of Amyloid‐β Peptides
Goldsbury, C., Mocanu, M., Thies, E., Kaether, C., Haass, C., Keller, P., Biernat, J., Mandelkow, E., & Mandelkow, E. (2006) · Traffic · doi:10.1111/j.1600-0854.2006.00434.x · Cited by 82 · see citing works
Self-citationReis, G. F., Yang, G., Szpankowski, L., Weaver, C., Shah, S. B., Robinson, J. T., Hays, T. S., Danuser, G., & Goldstein, L. S. B. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-11-0938 · Cited by 80 · see citing works
Transcriptional and conformational changes of the tau molecule in Alzheimer's disease
Hyman, B. T., Augustinack, J. C., & Ingelsson, M. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.06.015 · Cited by 79 · see citing works
Yoshiyama, Y., Zhang, B., Bruce, J., Trojanowski, J. Q., & Lee, V. M.-Y. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-33-10662.2003 · Cited by 72 · see citing works
The septo-hippocampal system, learning and recovery of function
Niewiadomska, G., Baksalerska-Pazera, M., & Riedel, G. (2009) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2009.03.039 · Cited by 67 · see citing works
Rhein, V., & Eckert, A. (2007) · Archives of Physiology and Biochemistry · doi:10.1080/13813450701572288 · Cited by 56 · see citing works
Mitochondrial dynamics in aging and disease
Bereiter-Hahn, J. (2014) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-394625-6.00004-0 · Cited by 48 · see citing works
Hyperphosphorylated tau is a cause of neuronal dysfunction in tauopathy
Takashima, A. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-14403 · Cited by 40 · see citing works
Montesanto, A., Crocco, P., Anfossi, M., Smirne, N., Puccio, G., Colao, R., Maletta, R., Passarino, G., Bruni, A. C., & Rose, G. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150993 · Cited by 24 · see citing works
Retromer dysfunction at the nexus of tauopathies
Carosi, J. M., Denton, D., Kumar, S., & Sargeant, T. J. (2021) · Cell Death & Differentiation · doi:10.1038/s41418-020-00727-2 · Cited by 16 · see citing works
Torres-Cruz, F. M., Rodríguez-Cruz, F., Escobar-Herrera, J., Barragán-Andrade, N., Basurto-Islas, G., Ripova, D., Ávila, J., & Garcia-Sierra, F. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-150396 · Cited by 19 · see citing works
Beaudet, D., Berger, C. L., & Hendricks, A. G. (2026) · eLife · doi:10.7554/elife.110011
- Authors
- Stamer, K., Vogel, R., Thies, E., Mandelkow, E., & Mandelkow, E.-M.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Max-Planck-Unit for Structural Molecular Biology, 22607 Hamburg, Germany
- ORCID
- Thies, E.
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2002-03-18
- Volume
- 156
- Issue
- 6
- Pages
- 1051-1063
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2173473
- OpenAlex
- W2117526022
- Cited by
- 885
- References
- 4
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 28 · 2023: 24 · 2022: 39 · 2021: 27 · 2020: 55 · 2019: 36 · 2018: 32 · 2017: 31 · 2016: 39 · 2015: 28 · 2014: 34 · 2013: 43 · 2012: 55
- FWCI
- 24.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Cell Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Universität Heidelberg
- KU Leuven
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- tau protein, microtubule-associated proteins, intracellular trafficking, peroxisomes, neurofilaments, amyloid precursor protein, oxidative stress, neurodegeneration, axonal transport, Golgi-derived vesicles, Alzheimer's disease, cortical neurons, retinal ganglion cells
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cell Survival, Cerebral Cortex, Chick Embryo, Fluorescent Antibody Technique, Gene Expression Regulation, Golgi Apparatus, Humans, Mitochondria, Retinal Ganglion Cells, Time Factors, Tumor Cells, Cultured, Organelles, Neurites, Amyloid beta-Protein Precursor, tau Proteins, Neurofilament Proteins, Oxidative Stress, Peroxisomes, Protein Transport, Transport Vesicles, Mice, Rats
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