The role of tau Oligomers in the onset of Alzheimer's disease neuropathology

ACS Chemical Neuroscience

Volumn 5, Issue 12, 2014, Pages 1178-1191

  Cárdenas Aguayo, María Del Carmen ^a   Gómez Virgilio, Laura ^a   DeRosa, Steven ^b   Meraz Ríos, Marco Antonio ^a  

^a DEPARTAMENTO DE FÍSICA   (Mexico)

^b NATHAN S KLINE INSTITUTE FOR PSYCHIATRIC RESEARCH   (United States)

Author keywords

Aggregation; Alzheimer's disease; Autophagy; Neurodegeneration; New drug targets; Proteasome; Protein spreading; Synaptic impairment; Tau oligomers

Indexed keywords

OLIGOMER; PROTEASOME; TAU OLIGOMER; TAU PROTEIN; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; AUTOPHAGY; HISTOPATHOLOGY; HUMAN; MEMORY; NERVE FIBER TRANSPORT; NEUROFIBRILLARY TANGLE; NEUROPATHOLOGY; NEUROPROTECTION; NEUROTOXICITY; PAIRED HELICAL FILAMENT; PRION; PROTEIN AGGREGATION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REVIEW; TAUOPATHY; TURNOVER TIME; ANIMAL; BIOLOGICAL MODEL; BRAIN; CHEMISTRY; METABOLISM; PATHOLOGY;

ALZHEIMER DISEASE; ANIMALS; BRAIN; HUMANS; MODELS, BIOLOGICAL; TAU PROTEINS;

EID: 84918529724     PISSN: None     EISSN: 19487193     Source Type: Journal    
DOI: 10.1021/cn500148z     Document Type: Review

References (146)

1. Hebert, L. E., Weuve, J., Scherr, P. A., and Evans, D. A. (2013) Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 80, 1778-1783.
2. Greig, N. H., and Lahiri, D. K. (2014) Advances in understanding Alzheimer's disease, and the contributions of current Alzheimer research: ten years on and beyond. Curr. Alzheimer Res. 11, 107-109.
3. Riemer, J., and Kins, S. (2013) Axonal transport and mitochondrial dysfunction in Alzheimer's disease. Neurodegener. Dis. 12, 111-124.
4. Zambrano, C. A., Egana, J. T., Nunez, M. T., Maccioni, R. B., and Gonzalez-Billault, C. (2004) Oxidative stress promotes tau dephosphorylation in neuronal cells: the roles of cdk5 and PP1. Free Radical Biol. Med. 36, 1393-1402.
5. Maynard, C. J., Bush, A. I., Masters, C. L., Cappai, R., and Li, Q. X. (2005) Metals and amyloid-beta in Alzheimer's disease. Int. J. Exp. Pathol. 86, 147-159.
6. Reitz, C. (2013) Dyslipidemia and the risk of Alzheimer's disease. Curr. Atheroscler. Rep. 15, 307.
7. Zerovnik, E. (2010) Protein conformational pathology in Alzheimer's and other neurodegenerative diseases; new targets for therapy. Curr. Alzheimer Res. 7, 74-83.
8. Li, J. G., Chu, J., Barrero, C., Merali, S., and Pratico, D. (2014) Homocysteine exacerbates beta-amyloid pathology, tau pathology, and cognitive deficit in a mouse model of Alzheimer disease with plaques and tangles. Ann. Neurol. 75, 851-863.
9. Nazef, K., Khelil, M., Chelouti, H., Kacimi, G., Bendini, M., Tazir, M., Belarbi, S., El Hadi Cherifi, M., and Djerdjouri, B. (2014) Hyperhomocysteinemia is a risk factor for Alzheimer's disease in an Algerian population. Arch. Med. Res. 45, 247-250.
10. Gong, C. X., Grundke-Iqbal, I., and Iqbal, K. (2010) Targeting tau protein in Alzheimer's disease. Drugs Aging 27, 351-365.
11. Morales, I., Guzman-Martinez, L., Cerda-Troncoso, C., Farias, G. A., and Maccioni, R. B. (2014) Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. Front. Cell. Neurosci. 8, 112.
12. Meraz-Rios, M. A., Lira-De Leon, K. I., Campos-Pena, V., De Anda-Hernandez, M. A., and Mena-Lopez, R. (2010) Tau oligomers and aggregation in Alzheimer's disease. J. Neurochem. 112, 1353-1367.
13. Auer, I. A., Schmidt, M. L., Lee, V. M., Curry, B., Suzuki, K., Shin, R. W., Pentchev, P. G., Carstea, E. D., and Trojanowski, J. Q. (1995) Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer's disease. Acta Neuropathol. 90, 547-551.
14. Yang, L., and Ksiezak-Reding, H. (1998) Ubiquitin immunoreactivity of paired helical filaments differs in Alzheimer's disease and corticobasal degeneration. Acta Neuropathol. 96, 520-526.
15. Schmidt, M. L., Huang, R., Martin, J. A., Henley, J., Mawal-Dewan, M., Hurtig, H. I., Lee, V. M., and Trojanowski, J. Q. (1996) Neurofibrillary tangles in progressive supranuclear palsy contain the same tau epitopes identified in Alzheimer's disease PHFtau. J. Neuropathol. Exp. Neurol. 55, 534-539.
16. Mackenzie, I. R., and Rademakers, R. (2007) The molecular genetics and neuropathology of frontotemporal lobar degeneration: recent developments. Neurogenetics 8, 237-248.
17. Yamada, M. (2003) Senile dementia of the neurofibrillary tangle type (tangle-only dementia): neuropathological criteria and clinical guidelines for diagnosis. Neuropathology 23, 311-317.
18. Berger, Z., Roder, H., Hanna, A., Carlson, A., Rangachari, V., Yue, M., Wszolek, Z., Ashe, K., Knight, J., Dickson, D., Andorfer, C., Rosenberry, T. L., Lewis, J., Hutton, M., and Janus, C. (2007) Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J. Neurosci. 27, 3650-3662.
19. Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Sarmiento, J., Troncoso, J., Jackson, G. R., and Kayed, R. (2012) Identification of oligomers at early stages of tau aggregation in Alzheimer's disease. FASEB J. 26, 1946-1959.
20. Lasagna-Reeves, C. A., Sengupta, U., Castillo-Carranza, D., Gerson, J. E., Guerrero-Munoz, M., Troncoso, J. C., Jackson, G. R., and Kayed, R. (2014) The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes. Acta Neuropathol. Commun. 2, 56.
21. Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Clos, A. L., Jackson, G. R., and Kayed, R. (2011) Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Mol. Neurodegener. 6, 39.
22. Haass, C., and Selkoe, D. J. (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat. Rev. Mol. Cell Biol. 8, 101-112.
23. Ding, T. T., Lee, S. J., Rochet, J. C., and Lansbury, P. T., Jr. (2002) Annular alpha-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes. Biochemistry 41, 10209-10217.
24. Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T., and Lansbury, P. T., Jr. (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291.
25. Lasagna-Reeves, C. A., Glabe, C. G., and Kayed, R. (2011) Amyloid-beta annular protofibrils evade fibrillar fate in Alzheimer disease brain. J. Biol. Chem. 286, 22122-22130.
26. Wu, J. W., Herman, M., Liu, L., Simoes, S., Acker, C. M., Figueroa, H., Steinberg, J. I., Margittai, M., Kayed, R., Zurzolo, C., Di Paolo, G., and Duff, K. E. (2013) Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J. Biol. Chem. 288, 1856-1870.
27. Gerson, J. E., and Kayed, R. (2013) Formation and propagation of tau oligomeric seeds. Front. Neurol. 4, 93.
28. Lee, S., Kim, W., Li, Z., and Hall, G. F. (2012) Accumulation of vesicle-associated human tau in distal dendrites drives degeneration and tau secretion in an in situ cellular tauopathy model. Int. J. Alzheimer's Dis. 2012, 172837.
29. Neve, R. L., Harris, P., Kosik, K. S., Kurnit, D. M., and Donlon, T. A. (1986) Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. Brain Res. 387, 271-280.
30. Avila, J., Lucas, J. J., Perez, M., and Hernandez, F. (2004) Role of tau protein in both physiological and pathological conditions. Physiol. Rev. 84, 361-384.
31. Couchie, D., Mavilia, C., Georgieff, I. S., Liem, R. K., Shelanski, M. L., and Nunez, J. (1992) Primary structure of high molecular weight tau present in the peripheral nervous system. Proc. Natl. Acad. Sci. U.S.A. 89, 4378-4381.
32. Iqbal, K., Liu, F., Gong, C. X., and Grundke-Iqbal, I. (2010) Tau in Alzheimer disease and related tauopathies. Curr. Alzheimer Res. 7, 656-664.
33. Arrasate, M., Perez, M., and Avila, J. (2000) Tau dephosphorylation at tau-1 site correlates with its association to cell membrane. Neurochem. Res. 25, 43-50.
34. Trinczek, B., Biernat, J., Baumann, K., Mandelkow, E. M., and Mandelkow, E. (1995) Domains of tau protein, differential phosphorylation, and dynamic instability of microtubules. Mol. Biol. Cell 6, 1887-1902.
35. Chin, S. S., and Goldman, J. E. (1996) Glial inclusions in CNS degenerative diseases. J. Neuropathol. Exp. Neurol. 55, 499-508.
36. Brandt, R., Leger, J., and Lee, G. (1995) Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain. J. Cell Biol. 131, 1327-1340.
37. Ballatore, C., Lee, V. M., and Trojanowski, J. Q. (2007) Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat. Rev. Neurosci. 8, 663-672.
38. Wischik, C. M., Edwards, P. C., Lai, R. Y., Gertz, H. N., Xuereb, J. H., Paykel, E. S., Brayne, C., Huppert, F. A., Mukaetova-Ladinska, E. B., Mena, R., et al. (1995) Quantitative analysis of tau protein in paired helical filament preparations: implications for the role of tau protein phosphorylation in PHF assembly in Alzheimer's disease. Neurobiol. Aging 16, 409-417.
39. Luna-Munoz, J., Garcia-Sierra, F., Falcon, V., Menendez, I., Chavez-Macias, L., and Mena, R. (2005) Regional conformational change involving phosphorylation of tau protein at the Thr231, precedes the structural change detected by Alz-50 antibody in Alzheimer's disease. J. Alzheimers Dis. 8, 29-41.
40. Grundke-Iqbal, I., Iqbal, K., Tung, Y. C., Quinlan, M., Wisniewski, H. M., and Binder, L. I. (1986) Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U.S.A. 83, 4913-4917.
41. Bramblett, G. T., Goedert, M., Jakes, R., Merrick, S. E., Trojanowski, J. Q., and Lee, V. M. (1993) Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron 10, 1089-1099.
42. Alonso, A. C., Zaidi, T., Grundke-Iqbal, I., and Iqbal, K. (1994) Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 91, 5562-5566.
43. Feinstein, S. C., and 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.
44. Cowan, C. M., Chee, F., Shepherd, D., and Mudher, A. (2010) Disruption of neuronal function by soluble hyperphosphorylated tau in a Drosophila model of tauopathy. Biochem. Soc. Trans. 38, 564-570.
45. Luna-Munoz, J., Chavez-Macias, L., Garcia-Sierra, F., and Mena, R. (2007) Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer's disease. J. Alzheimer's Dis. 12, 365-375.
46. Bancher, C., Brunner, C., Lassmann, H., Budka, H., Jellinger, K., Wiche, G., Seitelberger, F., Grundke-Iqbal, I., Iqbal, K., and Wisniewski, H. M. (1989) Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res. 477, 90-99.
47. Makrides, V., Shen, T. E., Bhatia, R., Smith, B. L., Thimm, J., Lal, R., and Feinstein, S. C. (2003) Microtubule-dependent oligomerization of tau. Implications for physiological tau function and tauopathies. J. Biol. Chem. 278, 33298-33304.
48. Patterson, K. R., Remmers, C., Fu, Y., Brooker, S., Kanaan, N. M., Vana, L., Ward, S., Reyes, J. F., Philibert, K., Glucksman, M. J., and Binder, L. I. (2011) Characterization of prefibrillar tau oligomers in vitro and in Alzheimer disease. J. Biol. Chem. 286, 23063-23076.
49. Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Guerrero-Muoz, M. J., Jackson, G. R., and Kayed, R. (2010) Preparation and characterization of neurotoxic tau oligomers. Biochemistry 49, 10039-10041.
50. Cowan, C. M., Quraishe, S., and Mudher, A. (2012) What is the pathological significance of tau oligomers? Biochem. Soc. Trans. 40, 693-697.
51. Gerson, J. E., Sengupta, U., Lasagna-Reeves, C. A., Guerrero-Munoz, M. J., Troncoso, J., and Kayed, R. (2014) Characterization of tau oligomeric seeds in progressive supranuclear palsy. Acta Neuropathol. Commun. 2, 73.
52. Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., and Glabe, C. G. (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486-489.
53. Caughey, B., Baron, G. S., Chesebro, B., and Jeffrey, M. (2009) Getting a grip on prions: oligomers, amyloids, and pathological membrane interactions. Ann. Rev. Biochem. 78, 177-204.
54. Soto, C. (2012) In vivo spreading of tau pathology. Neuron 73, 621-623.
55. Rosenmann, H., Blum, D., Kayed, R., and Ittner, L. M. (2012) Tau protein: function and pathology. Int. J. Alzheimer's Dis. 2012, 707482.
56. Iqbal, K., Gong, C. X., and Liu, F. (2013) Hyperphosphorylation-induced tau oligomers. Front. Neurol. 4, 112.
57. Alonso Adel, C., Mederlyova, A., Novak, M., Grundke-Iqbal, I., and Iqbal, K. (2004) Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J. Biol. Chem. 279, 34873-34881.
58. Liu, F., and Gong, C. X. (2008) Tau exon 10 alternative splicing and tauopathies. Mol. Neurodegener. 3, 8.
59. Kopke, E., Tung, Y. C., Shaikh, S., Alonso, A. C., Iqbal, K., and Grundke-Iqbal, I. (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J. Biol. Chem. 268, 24374-24384.
60. Wischik, C. M., Harrington, C. R., and Storey, J. M. (2014) Tau-aggregation inhibitor therapy for Alzheimer's disease. Biochem. Pharmacol. 88, 529-539.
61. Schneider, A., Biernat, J., von Bergen, M., Mandelkow, E., and Mandelkow, E. M. (1999) Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 38, 3549-3558.
62. Wischik, C. M., Novak, M., Thogersen, H. C., Edwards, P. C., Runswick, M. J., Jakes, R., Walker, J. E., Milstein, C., Roth, M., and Klug, A. (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 85, 4506-4510.
63. Novak, M., Kabat, J., and Wischik, C. M. (1993) Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament. EMBO J. 12, 365-370.
64. Mullane, K., and Williams, M. (2013) Alzheimer's therapeutics: continued clinical failures question the validity of the amyloid hypothesis-but what lies beyond? Biochem. Pharmacol. 85, 289-305.
65. Hardy, J. A., and Higgins, G. A. (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184-185.
66. Tabaton, M., Mandybur, T. I., Perry, G., Onorato, M., Autilio-Gambetti, L., and Gambetti, P. (1989) The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition. Ann. Neurol. 26, 771-778.
67. Hardy, J., and Selkoe, D. J. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356.
68. Ferreira, S. T., Vieira, M. N., and De Felice, F. G. (2007) Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases. IUBMB Life 59, 332-345.
69. Maccioni, R. B., Farias, G., Morales, I., and Navarrete, L. (2010) The revitalized tau hypothesis on Alzheimer's disease. Arch. Med. Res. 41, 226-231.
70. Crespo-Biel, N., Theunis, C., and Van Leuven, F. (2012) Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease. Int. J. Alzheimer's Dis. 2012, 251426.
71. Maeda, S., Sahara, N., Saito, Y., Murayama, S., Ikai, A., and Takashima, A. (2006) Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer's disease. Neurosci. Res. 54, 197-201.
72. Nixon, R. A. (2013) The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983-997.
73. Wang, X. J., Yu, J., Wong, S. H., Cheng, A. S., Chan, F. K., Ng, S. S., Cho, C. H., Sung, J. J., and Wu, W. K. (2013) A novel crosstalk between two major protein degradation systems: regulation of proteasomal activity by autophagy. Autophagy 9, 1500-1508.
74. Korolchuk, V. I., Menzies, F. M., and Rubinsztein, D. C. (2010) Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett. 584, 1393-1398.
75. Keck, S., Nitsch, R., Grune, T., and Ullrich, O. (2003) Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease. J. Neurochem. 85, 115-122.
76. Lee, M. J., Lee, J. H., and Rubinsztein, D. C. (2013) Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. Prog. Neurobiol. 105, 49-59.
77. Tai, H. C., Serrano-Pozo, A., Hashimoto, T., Frosch, M. P., Spires-Jones, T. L., and Hyman, B. T. (2012) The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am. J. Pathol. 181, 1426-1435.
78. Chesser, A. S., Pritchard, S. M., and Johnson, G. V. (2013) Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease. Front. Neurol. 4, 122.
79. David, D. C., Layfield, R., Serpell, L., Narain, Y., Goedert, M., and Spillantini, M. G. (2002) Proteasomal degradation of tau protein. J. Neurochem. 83, 176-185.
80. Babu, J. R., Geetha, T., and Wooten, M. W. (2005) Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J. Neurochem. 94, 192-203.
81. 2+-dependent proteasome protease system. J. Neural Transm. 112, 547-555.
82. Grune, T., Botzen, D., Engels, M., Voss, P., Kaiser, B., Jung, T., Grimm, S., Ermak, G., and Davies, K. J. (2010) Tau protein degradation is catalyzed by the ATP/ubiquitin-independent 20S proteasome under normal cell conditions. Arch. Biochem. Biophys. 500, 181-188.
83. Arawaka, S., Machiya, Y., and Kato, T. (2010) Heat shock proteins as suppressors of accumulation of toxic prefibrillar intermediates and misfolded proteins in neurodegenerative diseases. Curr. Pharm. Biotechnol. 11, 158-166.
84. Ali, Y. O., Ruan, K., and Zhai, R. G. (2012) NMNAT suppresses tau-induced neurodegeneration by promoting clearance of hyperphosphorylated tau oligomers in a Drosophila model of tauopathy. Hum. Mol. Genet. 21, 237-250.
85. Kruger, U., Wang, Y., Kumar, S., and Mandelkow, E. M. (2012) Autophagic degradation of tau in primary neurons and its enhancement by trehalose. Neurobiol. Aging 33, 2291-2305.
86. Cuervo, A. M. (2004) Autophagy: many paths to the same end. Mol. Cell. Biochem. 263, 55-72.
87. Bednarski, E., and Lynch, G. (1996) Cytosolic proteolysis of tau by cathepsin D in hippocampus following suppression of cathepsins B and L. J. Neurochem. 67, 1846-1855.
88. Bendiske, J., and Bahr, B. A. (2003) Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis - an approach for slowing Alzheimer disease? J. Neuropathol. Exp. Neurol. 62, 451-463.
89. Hamano, T., Gendron, T. F., Causevic, E., Yen, S. H., Lin, W. L., Isidoro, C., Deture, M., and Ko, L. W. (2008) Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur. J. Neurosci. 27, 1119-1130.
90. Khurana, V., Elson-Schwab, I., Fulga, T. A., Sharp, K. A., Loewen, C. A., Mulkearns, E., Tyynela, J., Scherzer, C. R., and Feany, M. B. (2010) Lysosomal dysfunction promotes cleavage and neurotoxicity of tau in vivo. PLoS Genet. 6, e1001026.
91. Wang, Y., Martinez-Vicente, M., Kruger, U., Kaushik, S., Wong, E., Mandelkow, E. M., Cuervo, A. M., and Mandelkow, E. (2009) Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum. Mol. Genet. 18, 4153-4170.
92. Congdon, E. E., Wu, J. W., Myeku, N., Figueroa, Y. H., Herman, M., Marinec, P. S., Gestwicki, J. E., Dickey, C. A., Yu, W. H., and Duff, K. E. (2012) Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy 8, 609-622.
93. Schaeffer, V., Lavenir, I., Ozcelik, S., Tolnay, M., Winkler, D. T., and Goedert, M. (2012) Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain 135, 2169-2177.
94. Berger, Z., Ravikumar, B., Menzies, F. M., Oroz, L. G., Underwood, B. R., Pangalos, M. N., Schmitt, I., Wullner, U., Evert, B. O., O'Kane, C. J., and Rubinsztein, D. C. (2006) Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433-442.
95. Inoue, K., Rispoli, J., Kaphzan, H., Klann, E., Chen, E. I., Kim, J., Komatsu, M., and Abeliovich, A. (2012) Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway. Mol. Neurodegener. 7, 48.
96. Wang, Y., and Mandelkow, E. (2012) Degradation of tau protein by autophagy and proteasomal pathways. Biochem. Soc. Trans. 40, 644-652.
97. Cuervo, A. M., and Dice, J. F. (2000) When lysosomes get old. Exp Gerontol. 35, 119-131.
98. Ward, W. F. (2002) Protein degradation in the aging organism. Prog. Mol. Subcell. Biol. 29, 35-42.
99. Terman, A. (1995) The effect of age on formation and elimination of autophagic vacuoles in mouse hepatocytes. Gerontology 41, 319-326.
100. Lee, S., Sato, Y., and Nixon, R. A. (2011) Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy. J. Neurosci. 31, 7817-7830.
101. Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., and Tanaka, K. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880-884.
102. Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., and Mizushima, N. (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885-889.
103. Nixon, R. A., Wegiel, J., Kumar, A., Yu, W. H., Peterhoff, C., Cataldo, A., and Cuervo, A. M. (2005) Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 64, 113-122.
104. Ihara, Y., Morishima-Kawashima, M., and Nixon, R. (2012) The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer disease. Cold Spring Harbor Perspect. Med. 2, a006361.
105. Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Guerrero-Munoz, M. J., Kiritoshi, T., Neugebauer, V., Jackson, G. R., and Kayed, R. (2012) Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci. Rep. 2, 700.
106. Frost, B., Jacks, R. L., and Diamond, M. I. (2009) Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem. 284, 12845-12852.
107. Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., Jucker, M., Goedert, M., and Tolnay, M. (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909-913.
108. Clavaguera, F., Lavenir, I., Falcon, B., Frank, S., Goedert, M., and Tolnay, M. (2013) "Prion-like" templated misfolding in tauopathies. Brain Pathol. 23, 342-349.
109. Liu, L., Drouet, V., Wu, J. W., Witter, M. P., Small, S. A., Clelland, C., and Duff, K. (2012) Trans-synaptic spread of tau pathology in vivo. PLoS One 7, e31302.
110. de Calignon, A., Polydoro, M., Suarez-Calvet, M., William, C., Adamowicz, D. H., Kopeikina, K. J., Pitstick, R., Sahara, N., Ashe, K. H., Carlson, G. A., Spires-Jones, T. L., and Hyman, B. T. (2012) Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73, 685-697.
111. Montoya, M., and Gouaux, E. (2003) Beta-barrel membrane protein folding and structure viewed through the lens of alpha-hemolysin. Biochim. Biophys. Acta 1609, 19-27.
112. LaPointe, N. E., Morfini, G., Pigino, G., Gaisina, I. N., Kozikowski, A. P., Binder, L. I., and Brady, S. T. (2009) The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity. J. Neurosci. Res. 87, 440-451.
113. Ward, S. M., Himmelstein, D. S., Lancia, J. K., and Binder, L. I. (2012) Tau oligomers and tau toxicity in neurodegenerative disease. Biochem. Soc. Trans. 40, 667-671.
114. Kanaan, N. M., Morfini, G. A., LaPointe, N. E., Pigino, G. F., Patterson, K. R., Song, Y., Andreadis, A., Fu, Y., Brady, S. T., and Binder, L. I. (2011) Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J. Neurosci. 31, 9858-9868.
115. Santacruz, K., Lewis, J., Spires, T., Paulson, J., Kotilinek, L., Ingelsson, M., Guimaraes, A., DeTure, M., Ramsden, M., McGowan, E., Forster, C., Yue, M., Orne, J., Janus, C., Mariash, A., Kuskowski, M., Hyman, B., Hutton, M., and Ashe, K. H. (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476-481.
116. Morsch, R., Simon, W., and Coleman, P. D. (1999) Neurons may live for decades with neurofibrillary tangles. J. Neuropathol. Exp. Neurol. 58, 188-197.
117. Sluchanko, N. N., and Gusev, N. B. (2011) Probable participation of 14-3-3 in tau protein oligomerization and aggregation. J. Alzheimer's Dis. 27, 467-476.
118. Castellani, R. J., Nunomura, A., Lee, H. G., Perry, G., and Smith, M. A. (2008) Phosphorylated tau: toxic, protective, or none of the above. J. Alzheimer's Dis. 14, 377-383.
119. Johnson, G. V., and Stoothoff, W. H. (2004) Tau phosphorylation in neuronal cell function and dysfunction. J. Cell Sci. 117, 5721-5729.
120. Alonso Adel, C., Li, B., Grundke-Iqbal, I., and Iqbal, K. (2006) Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. Proc. Natl. Acad. Sci. U.S.A. 103, 8864-8869.
121. Iqbal, K., Alonso Adel, C., and Grundke-Iqbal, I. (2008) Cytosolic abnormally hyperphosphorylated tau but not paired helical filaments sequester normal MAPs and inhibit microtubule assembly. J. Alzheimer's Dis. 14, 365-370.
122. Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P., and Kivipelto, M. (2010) Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 9, 702-716.
123. Wischik, C. M., Edwards, P. C., Lai, R. Y., Roth, M., and Harrington, C. R. (1996) Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc. Natl. Acad. Sci. U.S.A. 93, 11213-11218.
124. Oz, M., Lorke, D. E., and Petroianu, G. A. (2009) Methylene blue and Alzheimer's disease. Biochem. Pharmacol. 78, 927-932.
125. Lira-De Leon, K. I., Garcia-Gutierrez, P., Serratos, I. N., Palomera-Cardenas, M., Figueroa-Corona Mdel, P., Campos-Pena, V., and Meraz-Rios, M. A. (2013) Molecular mechanism of tau aggregation induced by anionic and cationic dyes. J. Alzheimer's Dis. 35, 319-334.
126. Wischik, C., and Staff, R. (2009) Challenges in the conduct of disease-modifying trials in AD: practical experience from a phase 2 trial of Tau-aggregation inhibitor therapy. J. Nutr. Health Aging 13, 367-369.
127. Duff, K., Kuret, J., and Congdon, E. E. (2010) Disaggregation of tau as a therapeutic approach to tauopathies. Curr. Alzheimer Res. 7, 235-240.
128. Akoury, E., Gajda, M., Pickhardt, M., Biernat, J., Soraya, P., Griesinger, C., Mandelkow, E., and Zweckstetter, M. (2013) Inhibition of tau filament formation by conformational modulation. J. Am. Chem. Soc. 135, 2853-2862.
129. Wang, J., Santa-Maria, I., Ho, L., Ksiezak-Reding, H., Ono, K., Teplow, D. B., and Pasinetti, G. M. (2010) Grape derived polyphenols attenuate tau neuropathology in a mouse model of Alzheimer's disease. J. Alzheimer's Dis. 22, 653-661.
130. Lee, B. H., Lee, M. J., Park, S., Oh, D. C., Elsasser, S., Chen, P. C., Gartner, C., Dimova, N., Hanna, J., Gygi, S. P., Wilson, S. M., King, R. W., and Finley, D. (2010) Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179-184.
131. Wolfe, D. M., Lee, J. H., Kumar, A., Lee, S., Orenstein, S. J., and Nixon, R. A. (2013) Autophagy failure in Alzheimer's disease and the role of defective lysosomal acidification. Eur. J. Neurosci. 37, 1949-1961.
132. McBrayer, M., and Nixon, R. A. (2013) Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime. Biochem. Soc. Trans. 41, 1495-1502.
133. Le Corre, S., Klafki, H. W., Plesnila, N., Hubinger, G., Obermeier, A., Sahagun, H., Monse, B., Seneci, P., Lewis, J., Eriksen, J., Zehr, C., Yue, M., McGowan, E., Dickson, D. W., Hutton, M., and Roder, H. M. (2006) An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 103, 9673-9678.
134. Panza, F., Solfrizzi, V., Frisardi, V., Imbimbo, B. P., Capurso, C., D'Introno, A., Colacicco, A. M., Seripa, D., Vendemiale, G., Capurso, A., and Pilotto, A. (2009) Beyond the neurotransmitter-focused approach in treating Alzheimer's disease: drugs targeting beta-amyloid and tau protein. Aging: Clin. Exp. Res. 21, 386-406.
135. Hampel, H., Ewers, M., Burger, K., Annas, P., Mortberg, A., Bogstedt, A., Frolich, L., Schroder, J., Schonknecht, P., Riepe, M. W., Kraft, I., Gasser, T., Leyhe, T., M?ller, H. J., Kurz, A., and Basun, H. (2009) Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J. Clin. Psychiatry 70, 922-931.
136. Kickstein, E., Krauss, S., Thornhill, P., Rutschow, D., Zeller, R., Sharkey, J., Williamson, R., Fuchs, M., Kohler, A., Glossmann, H., Schneider, R., Sutherland, C., and Schweiger, S. (2010) Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc. Natl. Acad. Sci. U.S.A. 107, 21830-21835.
137. van Eersel, J., Ke, Y. D., Liu, X., Delerue, F., Kril, J. J., Gotz, J., and Ittner, L. M. (2010) Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models. Proc. Natl. Acad. Sci. U.S.A. 107, 13888-13893.
138. Castillo-Carranza, D. L., Gerson, J. E., Sengupta, U., Guerrero-Munoz, M. J., Lasagna-Reeves, C. A., and Kayed, R. (2014) Specific targeting of tau oligomers in htau mice prevents cognitive impairment and tau toxicity following injection with brain-derived tau oligomeric seeds. J. Alzheimer's Dis. 40, S97-S111.
139. Castillo-Carranza, D. L., Sengupta, U., Guerrero-Munoz, M. J., Lasagna-Reeves, C. A., Gerson, J. E., Singh, G., Estes, D. M., Barrett, A. D., Dineley, K. T., Jackson, G. R., and Kayed, R. (2014) Passive immunization with tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J. Neurosci. 34, 4260-4272.
140. Asuni, A. A., Boutajangout, A., Quartermain, D., and Sigurdsson, E. M. (2007) Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J. Neurosci. 27, 9115-9129.
141. Bi, M., Ittner, A., Ke, Y. D., Gotz, J., and Ittner, L. M. (2011) Tau-targeted immunization impedes progression of neurofibrillary histopathology in aged P301L tau transgenic mice. PLoS One 6, e26860.
142. Boimel, M., Grigoriadis, N., Lourbopoulos, A., Haber, E., Abramsky, O., and Rosenmann, H. (2010) Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice. Exp. Neurol. 224, 472-485.
143. Boutajangout, A., Quartermain, D., and Sigurdsson, E. M. (2010) Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J. Neurosci. 30, 16559-16566.
144. Boutajangout, A., Ingadottir, J., Davies, P., and Sigurdsson, E. M. (2011) Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J. Neurochem. 118, 658-667.
145. Chai, X., Wu, S., Murray, T. K., Kinley, R., Cella, C. V., Sims, H., Buckner, N., Hanmer, J., Davies, P., O'Neill, M. J., Hutton, M. L., and Citron, M. (2011) Passive immunization with anti-Tau antibodies in two transgenic models: reduction of tau pathology and delay of disease progression. J. Biol. Chem. 286, 34457-34467.
146. Troquier, L., Caillierez, R., Burnouf, S., Fernandez-Gomez, F. J., Grosjean, M. E., Zommer, N., Sergeant, N., Schraen-Maschke, S., Blum, D., and Buee, L. (2012) Targeting phospho-Ser422 by active tau immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach. Curr. Alzheimer Res. 9, 397-405.