New features about tau function and dysfunction

Biomolecules

Volumn 6, Issue 2, 2016, Pages

  Medina, Miguel ^a,b   Hernández, Félix ^a,c   Avila, Jesús ^a,c  

^a CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED SOBRE ENFERMEDADES NEURODEGENERATIVAS CIBERNED   (Spain)

^b Instituto de Salud Carlos III   (Spain)

^c CENTRO DE BIOLOGÍA MOLECULAR SEVERO OCHOA   (Spain)

Author keywords

Alzheimer s disease; Immunotherapy; Neurodegeneration; Spreading; Tau; Tauopathies

Indexed keywords

AMYLOID PRECURSOR PROTEIN; GLYCOGEN SYNTHASE KINASE 3; TAU PROTEIN; MICRORNA; MONOCLONAL ANTIBODY;

ALZHEIMER DISEASE; BEHAVIOR DISORDER; DEGENERATIVE DISEASE; ELECTROPHORETIC MOBILITY; GENE OVEREXPRESSION; HUMAN; IMMUNIZATION; IMMUNOTHERAPY; LONG TERM DEPRESSION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PROTEIN PROCESSING; PROTEIN STRUCTURE, FUNCTION AND VARIABILITY; REVIEW; SIGNAL TRANSDUCTION; TAUOPATHY; ANIMAL; ANTAGONISTS AND INHIBITORS; GENETICS; METABOLISM; PATHOLOGY; RISK FACTOR;

ALZHEIMER DISEASE; ANIMALS; ANTIBODIES, MONOCLONAL; HUMANS; IMMUNOTHERAPY; MICRORNAS; RISK FACTORS; TAU PROTEINS;

EID: 85012065303     PISSN: None     EISSN: 2218273X     Source Type: Journal    
DOI: 10.3390/biom6020021     Document Type: Review

References (105)

1. Dustin, P. Microtubules (Second Totally Revised Edition); Springer-Verlag: Berlin, Heidelberg, Germany; New York, NY, USA; Tokyo, Japan, 1984.
2. Matus, A. Microtubule-associated proteins: Their potential role in determining neuronal morphology. Annu. Rev. Neurosci. 1988, 11, 29–44.
3. Avila, J. Microtubule dynamics. FASEB J. 1990, 4, 3284–3290.
4. Weingarten, M.D.; Lockwood, A.H.; Hwo, S.Y.; Kirschner, M.W. A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. USA 1975, 72, 1858–1862.
5. Conrad, C.; Vianna, C.; Freeman, M.; Davies, P. A polymorphic gene nested within an intron of the tau gene: Implications for Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2002, 99, 7751–7756.
6. Fellous, A.; Francon, J.; Lennon, A.M.; Nunez, J. Microtubule assembly in vitro. Purification of assembly-promoting factors. Eur. J. Biochem. 1977, 78, 167–174.
7. Binder, L.I.; Frankfurter, A.; Rebhun, L.I. The distribution of tau in the mammalian central nervous system. J. Cell Biol. 1985, 101, 1371–1378.
8. Serrano, L.; Montejo de Garcini, E.; Hernandez, M.A.; Avila, J. Localization of the tubulin binding site for tau protein. Eur. J. Biochem. 1985, 153, 595–600.
9. Grundke-Iqbal, I.; Iqbal, K.; Tung, Y.C.; Quinlan, M.; Wisniewski, H.M.; Binder, L.I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. USA 1986, 83, 4913–4917.
10. Grundke-Iqbal, I.; Iqbal, K.; Quinlan, M.; Tung, Y.C.; Zaidi, M.S.; Wisniewski, H.M. Microtubule-associated protein tau. A component of alzheimer paired helical filaments. J. Biol. Chem. 1986, 261, 6084–6089.
11. Kosik, K.S.; Joachim, C.L.; Selkoe, D.J. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in alzheimer disease. Proc. Natl. Acad. Sci. USA 1986, 83, 4044–4048.
12. Wood, J.G.; Mirra, S.S.; Pollock, N.J.; Binder, L.I. Neurofibrillary tangles of alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau). Proc. Natl. Acad. Sci. USA 1986, 83, 4040–4043.
13. Ihara, Y.; Nukina, N.; Miura, R.; Ogawara, M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer’s disease. J. Biochem. 1986, 99, 1807–1810.
14. Montejo de Garcini, E.; Carrascosa, J.L.; Correas, I.; Nieto, A.; Avila, J. Tau factor polymers are similar to paired helical filaments of Alzheimer’s disease. FEBS Lett. 1988, 236, 150–154.
15. Montejo de Garcini, E.; Serrano, L.; Avila, J. Self assembly of microtubule associated protein tau into filaments resembling those found in alzheimer disease. Biochem. Biophys. Res. Commun. 1986, 141, 790–796.
16. Wischik, C.M.; Novak, M.; Edwards, P.C.; Klug, A.; Tichelaar, W.; Crowther, R.A. Structural characterization of the core of the paired helical filament of alzheimer disease. Proc. Natl. Acad. Sci. USA 1988, 85, 4884–4888.
17. Wischik, C.M.; Novak, M.; Thogersen, H.C.; Edwards, P.C.; Runswick, M.J.; Jakes, R.; Walker, J.E.; Milstein, C.; Roth, M.; Klug, A. Isolation of a fragment of tau derived from the core of the paired helical filament of alzheimer disease. Proc. Natl. Acad. Sci. USA 1988, 85, 4506–4510.
18. Goedert, M.; Wischik, C.M.; Crowther, R.A.; Walker, J.E.; Klug, A. Cloning and sequencing of the cdna encoding a core protein of the paired helical filament of alzheimer disease: Identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. USA 1988, 85, 4051–4055.
19. Avila, J.; Lucas, J.J.; Perez, M.; Hernandez, F. Role of tau protein in both physiological and pathological conditions. Physiol. Rev. 2004, 84, 361–384.
20. Caceres, A.; Kosik, K.S. Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons. Nature 1990, 343, 461–463.
21. Drubin, D.G.; Kirschner, M.W. Tau protein function in living cells. J. Cell Biol. 1986, 103, 2739–2746.
22. Santa-Maria, I.; Hernandez, F.; del Rio, J.; Moreno, F.J.; Avila, J. Tramiprosate, a drug of potential interest for the treatment of Alzheimer’s disease, promotes an abnormal aggregation of tau. Mol. Neurodegener. 2007, 2, 17.
23. Santa-Maria, I.; Alaniz, M.E.; Renwick, N.; Cela, C.; Fulga, T.A.; van Vactor, D.; Tuschl, T.; Clark, L.N.; Shelanski, M.L.; McCabe, B.D.; et al. Dysregulation of microrna-219 promotes neurodegeneration through post-transcriptional regulation of tau. J. Clin. Investig. 2015, 125, 681–686.
24. Sayas, C.L.; Tortosa, E.; Bollati, F.; Ramirez-Rios, S.; Arnal, I.; Avila, J. Tau regulates the localization and function of end-binding proteins 1 and 3 (EB1/3) in developing neuronal cells. J. Neurochem. 2015, 133, 653–667.
25. Dawson, H.N.; Ferreira, A.; Eyster, M.V.; Ghoshal, N.; Binder, L.I.; Vitek, M.P. Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J. Cell Sci. 2001, 114, 1179–1187.
26. Lei, P.; Ayton, S.; Finkelstein, D.I.; Spoerri, L.; Ciccotosto, G.D.; Wright, D.K.; Wong, B.X.; Adlard, P.A.; Cherny, R.A.; Lam, L.Q.; et al. Tau deficiency induces parkinsonism with dementia by impairing app-mediated iron export. Nat. Med. 2012, 18, 291–295.
27. Medina, M.; Avila, J. Further understanding of tau phosphorylation: Implications for therapy. Expert Rev. Neurother. 2015, 15, 115–122.
28. Regan, P.; Piers, T.; Yi, J.H.; Kim, D.H.; Huh, S.; Park, S.J.; Ryu, J.H.; Whitcomb, D.J.; Cho, K. Tau phosphorylation at serine 396 residue is required for hippocampal LTD. J. Neurosci. 2015, 35, 4804–4812.
29. Cook, C.; Stankowski, J.N.; Carlomagno, Y.; Stetler, C.; Petrucelli, L. Acetylation: A new key to unlock tau’s role in neurodegeneration. Alzheimers Res. Ther. 2014, 6, 29.
30. Cohen, T.J.; Friedmann, D.; Hwang, A.W.; Marmorstein, R.; Lee, V.M. The microtubule-associated tau protein has intrinsic acetyltransferase activity. Nat. Struct. Mol. Biol. 2013, 20, 756–762.
31. Menkes-Caspi, N.; Yamin, H.G.; Kellner, V.; Spires-Jones, T.L.; Cohen, D.; Stern, E.A. Pathological tau disrupts ongoing network activity. Neuron 2015, 85, 959–966.
32. Gao, L.; Tse, S.W.; Conrad, C.; Andreadis, A. Saitohin, which is nested in the tau locus and confers allele-specific susceptibility to several neurodegenerative diseases, interacts with peroxiredoxin 6. J. Biol. Chem. 2005, 280, 39268–39272.
33. Harada, A.; Oguchi, K.; Okabe, S.; Kuno, J.; Terada, S.; Ohshima, T.; Sato-Yoshitake, R.; Takei, Y.; Noda, T.; Hirokawa, N. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 1994, 369, 488–491.
34. Barton, A.J.; Harrison, P.J.; Najlerahim, A.; Heffernan, J.; McDonald, B.; Robinson, J.R.; Davies, D.C.; Harrison, W.J.; Mitra, P.; Hardy, J.A.; et al. Increased tau messenger rna in Alzheimer’s disease hippocampus. Am. J. Pathol. 1990, 137, 497–502.
35. Khatoon, S.; Grundke-Iqbal, I.; Iqbal, K. 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. 1992, 59, 750–753.
36. Myeku, N.; Clelland, C.L.; Emrani, S.; Kukushkin, N.V.; Yu, W.H.; Goldberg, A.L.; Duff, K.E. Tau-driven 26s proteasome impairment and cognitive dysfunction can be prevented early in disease by activating camp-pka signaling. Nat. Med. 2016, 22, 46–53.
37. Goedert, M.; Spillantini, M.G. Tau gene mutations and neurodegeneration. Biochem. Soc. Symp. 2001, 67, 59–71.
38. Lu, M.; Kosik, K.S. Competition for microtubule-binding with dual expression of tau missense and splice isoforms. Mol. Biol. Cell 2001, 12, 171–184.
39. Couchie, D.; Mavilia, C.; Georgieff, I.S.; Liem, R.K.; Shelanski, M.L.; Nunez, J. Primary structure of high molecular weight tau present in the peripheral nervous system. Proc. Natl. Acad. Sci. USA 1992, 89, 4378–4381.
40. Orr, M.E.; Garbarino, V.R.; Salinas, A.; Buffenstein, R. Sustained high levels of neuroprotective, high molecular weight, phosphorylated tau in the longest-lived rodent. Neurobiol. Aging 2015, 36, 1496–1504.
41. Perez, M.; Hernandez, F.; Lim, F.; Diaz-Nido, J.; Avila, J. Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J. Alzheimers Dis. 2003, 5, 301–308.
42. Noble, W.; Planel, E.; Zehr, C.; Olm, V.; Meyerson, J.; Suleman, F.; Gaynor, K.; Wang, L.; LaFrancois, J.; Feinstein, B.; et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc. Natl. Acad. Sci. USA 2005, 102, 6990–6995.
43. Moszczynski, A.J.; Gohar, M.; Volkening, K.; Leystra-Lantz, C.; Strong, W.; Strong, M.J. Thr175-phosphorylated tau induces pathologic fibril formation via GSK3beta-mediated phosphorylation of Thr231 in vitro. Neurobiol. Aging 2015, 36, 1590–1599.
44. Kamah, A.; Huvent, I.; Cantrelle, F.X.; Qi, H.; Lippens, G.; Landrieu, I.; Smet-Nocca, C. Nuclear magnetic resonance analysis of the acetylation pattern of the neuronal tau protein. Biochemistry 2014, 53, 3020–3032.
45. Min, S.W.; Chen, X.; Tracy, T.E.; Li, Y.; Zhou, Y.; Wang, C.; Shirakawa, K.; Minami, S.S.; Defensor, E.; Mok, S.A.; et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat. Med. 2015, 21, 1154–1162.
46. Sarnat, H.B.; Flores-Sarnat, L. Infantile tauopathies: Hemimegalencephaly; tuberous sclerosis complex; focal cortical dysplasia 2; ganglioglioma. Brain Dev. 2015, 37, 553–562.
47. Patterson, D.; Costa, A.C. Down syndrome and genetics—A case of linked histories. Nat. Rev. Genet. 2005, 6, 137–147.
48. Deidda, G.; Parrini, M.; Naskar, S.; Bozarth, I.F.; Contestabile, A.; Cancedda, L. Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of down syndrome. Nat. Med. 2015, 21, 318–326.
49. Ittner, L.M.; Ke, Y.D.; Delerue, F.; Bi, M.; Gladbach, A.; van Eersel, J.; Wolfing, H.; Chieng, B.C.; Christie, M.J.; Napier, I.A.; et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 2010, 142, 387–397.
50. Goedert, M.; Jakes, R. Mutations causing neurodegenerative tauopathies. Biochim. Biophys. Acta 2005, 1739, 240–250.
51. Marshall, C.R.; Guerreiro, R.; Thust, S.; Fletcher, P.; Rohrer, J.D.; Fox, N.C. A novel mapt mutation causing corticobasal syndrome led by progressive apraxia of speech. J. Alzheimers Dis. 2015, 48, 923–926.
52. Simon-Sanchez, J.; Schulte, C.; Bras, J.M.; Sharma, M.; Gibbs, J.R.; Berg, D.; Paisan-Ruiz, C.; Lichtner, P.; Scholz, S.W.; Hernandez, D.G.; et al. Genome-wide association study reveals genetic risk underlying parkinson’s disease. Nat. Genet. 2009, 41, 1308–1312.
53. Edwards, T.L.; Scott, W.K.; Almonte, C.; Burt, A.; Powell, E.H.; Beecham, G.W.; Wang, L.; Zuchner, S.; Konidari, I.; Wang, G.; et al. Genome-wide association study confirms SNPs in SNCA and the mapt region as common risk factors for parkinson disease. Ann. Hum. Genet. 2010, 74, 97–109.
54. Gomez-Ramos, A.; Diaz-Hernandez, M.; Cuadros, R.; Hernandez, F.; Avila, J. Extracellular tau is toxic to neuronal cells. FEBS Lett. 2006, 580, 4842–4850.
55. Gomez-Ramos, A.; Diaz-Hernandez, M.; Rubio, A.; Miras-Portugal, M.T.; Avila, J. Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol. Cell. Neurosci. 2008, 37, 673–681.
56. Clavaguera, F.; Bolmont, T.; Crowther, R.A.; Abramowski, D.; Frank, S.; Probst, A.; Fraser, G.; Stalder, A.K.; Beibel, M.; Staufenbiel, M.; et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 2009, 11, 909–913.
57. 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.; et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 2012, 73, 685–697.
58. Alonso, A.C.; Grundke-Iqbal, I.; Iqbal, K. Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat. Med. 1996, 2, 783–787.
59. Alonso, A.D.; di Clerico, J.; Li, B.; Corbo, C.P.; Alaniz, M.E.; Grundke-Iqbal, I.; Iqbal, K. Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration. J. Biol. Chem. 2010, 285, 30851–30860.
60. Flores-Rodriguez, P.; Ontiveros-Torres, M.A.; Cardenas-Aguayo, M.C.; Luna-Arias, J.P.; Meraz-Rios, M.A.; Viramontes-Pintos, A.; Harrington, C.R.; Wischik, C.M.; Mena, R.; Floran-Garduno, B.; et al. The relationship between truncation and phosphorylation at the c-terminus of tau protein in the paired helical filaments of Alzheimer’s disease. Front. Neurosci. 2015, 9, 33.
61. Fontaine, S.N.; Sabbagh, J.J.; Baker, J.; Martinez-Licha, C.R.; Darling, A.; Dickey, C.A. Cellular factors modulating the mechanism of tau protein aggregation. Cell. Mol. Life Sci. 2015, 72, 1863–1879.
62. Caillet-Boudin, M.L.; Buee, L.; Sergeant, N.; Lefebvre, B. Regulation of human MAPT gene expression. Mol. Neurodegener. 2015, 10, 28.
63. Derisbourg, M.; Leghay, C.; Chiappetta, G.; Fernandez-Gomez, F.J.; Laurent, C.; Demeyer, D.; Carrier, S.; Buee-Scherrer, V.; Blum, D.; Vinh, J.; et al. Role of the tau n-terminal region in microtubule stabilization revealed by new endogenous truncated forms. Sci. Rep. 2015, 5, 9659.
64. Corsetti, V.; Florenzano, F.; Atlante, A.; Bobba, A.; Ciotti, M.T.; Natale, F.; Della Valle, F.; Borreca, A.; Manca, A.; Meli, G.; et al. NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of parkin and UCHL-1: Implications in Alzheimer’s disease. Hum. Mol. Genet. 2015, 24, 3058–3081.
65. Matsumoto, S.E.; Motoi, Y.; Ishiguro, K.; Tabira, T.; Kametani, F.; Hasegawa, M.; Hattori, N. The twenty-four KDa C-terminal tau fragment increases with aging in tauopathy mice: Implications of prion-like properties. Hum. Mol. Genet. 2015, 24, 6403–6416.
66. Dubey, J.; Ratnakaran, N.; Koushika, S.P. Neurodegeneration and microtubule dynamics: Death by a thousand cuts. Front. Cell. Neurosci. 2015, 9, 343.
67. Fernandez-Nogales, M.; Cabrera, J.R.; Santos-Galindo, M.; Hoozemans, J.J.; Ferrer, I.; Rozemuller, A.J.; Hernandez, F.; Avila, J.; Lucas, J.J. Huntington’s disease is a four-repeat tauopathy with tau nuclear rods. Nat. Med. 2014, 20, 881–885.
68. Braak, H.; Braak, E. Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol. 1991, 1, 213–216.
69. Medina, M.; Avila, J. The role of extracellular tau in the spreading of neurofibrillary pathology. Front. Cell. Neurosci. 2014, 8, 113.
70. Clavaguera, F.; Hench, J.; Goedert, M.; Tolnay, M. Invited review: Prion-like transmission and spreading of tau pathology. Neuropathol. Appl. Neurobiol. 2015, 41, 47–58.
71. Ballatore, C.; Lee, V.M.; Trojanowski, J.Q. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci. 2007, 8, 663–672.
72. Hoover, B.R.; Reed, M.N.; Su, J.; Penrod, R.D.; Kotilinek, L.A.; Grant, M.K.; Pitstick, R.; Carlson, G.A.; Lanier, L.M.; Yuan, L.L.; et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010, 68, 1067–1081.
73. Koleske, A.J. Molecular mechanisms of dendrite stability. Nat. Rev. Neurosci. 2013, 14, 536–550.
74. Pooler, A.M.; Noble, W.; Hanger, D.P. A role for tau at the synapse in Alzheimer’s disease pathogenesis. Neuropharmacology 2014, 76 Pt A, 1–8.
75. Sokolow, S.; Henkins, K.M.; Bilousova, T.; Gonzalez, B.; Vinters, H.V.; Miller, C.A.; Cornwell, L.; Poon, W.W.; Gylys, K.H. Pre-synaptic C-terminal truncated tau is released from cortical synapses in Alzheimer’s disease. J. Neurochem. 2015, 133, 368–379.
76. Liu, L.; Drouet, V.; Wu, J.W.; Witter, M.P.; Small, S.A.; Clelland, C.; Duff, K. Trans-synaptic spread of tau pathology in vivo. PLoS ONE 2012, 7, e31302.
77. Rabano, A.; Rodal, I.; Cuadros, R.; Calero, M.; Hernandez, F.; Avila, J. Argyrophilic grain pathology as a natural model of tau propagation. J. Alzheimers Dis. 2014, 40, S123–S133.
78. Iba, M.; Guo, J.L.; McBride, J.D.; Zhang, B.; Trojanowski, J.Q.; Lee, V.M. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J. Neurosci. 2013, 33, 1024–1037.
79. Kfoury, N.; Holmes, B.B.; Jiang, H.; Holtzman, D.M.; Diamond, M.I. Trans-cellular propagation of tau aggregation by fibrillar species. J. Biol. Chem. 2012, 287, 19440–19451.
80. Dujardin, S.; Lecolle, K.; Caillierez, R.; Begard, S.; Zommer, N.; Lachaud, C.; Carrier, S.; Dufour, N.; Auregan, G.; Winderickx, J.; et al. Neuron-to-neuron wild-type tau protein transfer through a trans-synaptic mechanism: Relevance to sporadic tauopathies. Acta Neuropathol. Commun. 2014, 2, 14.
81. Calafate, S.; Buist, A.; Miskiewicz, K.; Vijayan, V.; Daneels, G.; de Strooper, B.; de Wit, J.; Verstreken, P.; Moechars, D. Synaptic contacts enhance cell-to-cell tau pathology propagation. Cell Rep. 2015, 11, 1176–1183.
82. Asai, H.; Ikezu, S.; Tsunoda, S.; Medalla, M.; Luebke, J.; Haydar, T.; Wolozin, B.; Butovsky, O.; Kugler, S.; Ikezu, T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 2015, 18, 1584–1593.
83. Lei, P.; Ayton, S.; Appukuttan, A.T.; Volitakis, I.; Adlard, P.A.; Finkelstein, D.I.; Bush, A.I. Clioquinol rescues parkinsonism and dementia phenotypes of the tau knockout mouse. Neurobiol. Dis. 2015, 81, 168–175.
84. Corbel, C.; Zhang, B.; Le Parc, A.; Baratte, B.; Colas, P.; Couturier, C.; Kosik, K.S.; Landrieu, I.; Le Tilly, V.; Bach, S. Tamoxifen inhibits CDK5 kinase activity by interacting with p35/p25 and modulates the pattern of tau phosphorylation. Chem. Biol. 2015, 22, 472–482.
85. Del Ser, T.; Steinwachs, K.C.; Gertz, H.J.; Andres, M.V.; Gomez-Carrillo, B.; Medina, M.; Vericat, J.A.; Redondo, P.; Fleet, D.; Leon, T. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: A pilot study. J. Alzheimers Dis. 2013, 33, 205–215.
86. Lovestone, S.; Boada, M.; Dubois, B.; Hull, M.; Rinne, J.O.; Huppertz, H.J.; Calero, M.; Andres, M.V.; Gomez-Carrillo, B.; Leon, T.; et al. A phase II trial of tideglusib in Alzheimer’s disease. J. Alzheimers Dis. 2015, 45, 75–88.
87. Zhang, Z.; Song, M.; Liu, X.; Kang, S.S.; Kwon, I.S.; Duong, D.M.; Seyfried, N.T.; Hu, W.T.; Liu, Z.; Wang, J.Z.; et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat. Med. 2014, 20, 1254–1262.
88. Wischik, C.M.; Staff, R.T.; Wischik, D.J.; Bentham, P.; Murray, A.D.; Storey, J.M.; Kook, K.A.; Harrington, C.R. Tau aggregation inhibitor therapy: An exploratory phase 2 study in mild or moderate Alzheimer’s disease. J. Alzheimers Dis. 2015, 44, 705–720.
89. Paranjape, S.R.; Riley, A.P.; Somoza, A.D.; Oakley, C.E.; Wang, C.C.; Prisinzano, T.E.; Oakley, B.R.; Gamblin, T.C. Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro. ACS Chem. Neurosci. 2015, 6, 751–760.
90. Seripa, D.; Solfrizzi, V.; Imbimbo, B.P.; Daniele, A.; Santamato, A.; Lozupone, M.; Zuliani, G.; Greco, A.; Logroscino, G.; Panza, F. Tau-directed approaches for the treatment of Alzheimer’s disease: Focus on leuco-methylthioninium. Expert Rev. Neurother. 2016, 16, 259–277.
91. DeFelipe, J. The dendritic spine story: An intriguing process of discovery. Front. Neuroanat. 2015, 9, 14.
92. Avale, M.E.; Rodriguez-Martin, T.; Gallo, J.M. Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing. Hum. Mol. Genet. 2013, 22, 2603–2611.
93. Poepsel, S.; Sprengel, A.; Sacca, B.; Kaschani, F.; Kaiser, M.; Gatsogiannis, C.; Raunser, S.; Clausen, T.; Ehrmann, M. Determinants of amyloid fibril degradation by the PDZ protease HTRA1. Nat. Chem. Biol. 2015, 11, 862–869.
94. Medina, M. Recent developments in tau-based therapeutics for neurodegenerative diseases. Recent Pat. CNS Drug Discov. 2011, 6, 20–30.
95. Golde, T.E.; Lewis, J.; McFarland, N.R. Anti-tau antibodies: Hitting the target. Neuron 2013, 80, 254–256.
96. Medina, M.; Avila, J. New perspectives on the role of tau in Alzheimer’s disease. Implications for therapy. Biochem. Pharmacol. 2014, 88, 540–547.
97. Sankaranarayanan, S.; Barten, D.M.; Vana, L.; Devidze, N.; Yang, L.; Cadelina, G.; Hoque, N.; DeCarr, L.; Keenan, S.; Lin, A.; et al. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. PLoS ONE 2015, 10, e0125614.
98. D’Abramo, C.; Acker, C.M.; Jimenez, H.; Davies, P. Passive immunization in JNPL3 transgenic mice using an array of phospho-tau specific antibodies. PLoS ONE 2015, 10, e0135774.
99. Kondo, A.; Shahpasand, K.; Mannix, R.; Qiu, J.; Moncaster, J.; Chen, C.H.; Yao, Y.; Lin, Y.M.; Driver, J.A.; Sun, Y.; et al. Antibody against early driver of neurodegeneration cis p-tau blocks brain injury and tauopathy. Nature 2015, 523, 431–436.
100. Wang, J.Z.; Zhang, Y. Configuration-specific immunotherapy targeting cis pThr231-Pro232 tau for alzheimer disease. J. Neurol. Sci. 2015, 348, 253–255.
101. Castillo-Carranza, D.L.; Guerrero-Munoz, M.J.; Sengupta, U.; Hernandez, C.; Barrett, A.D.; Dineley, K.; Kayed, R. Tau immunotherapy modulates both pathological tau and upstream amyloid pathology in an Alzheimer’s disease mouse model. J. Neurosci. 2015, 35, 4857–4868.
102. Yanamandra, K.; Kfoury, N.; Jiang, H.; Mahan, T.E.; Ma, S.; Maloney, S.E.; Wozniak, D.F.; Diamond, M.I.; Holtzman, D.M. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 2013, 80, 402–414.
103. Kontsekova, E.; Zilka, N.; Kovacech, B.; Novak, P.; Novak, M. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res. Ther. 2014, 6, 44.
104. Sigurdsson, E.M. Tau immunotherapy. Neurodegener. Dis. 2016, 16, 34–38.
105. Maruyama, M.; Shimada, H.; Suhara, T.; Shinotoh, H.; Ji, B.; Maeda, J.; Zhang, M.R.; Trojanowski, J.Q.; Lee, V.M.; Ono, M.; et al. Imaging of tau pathology in a tauopathy mouse model and in alzheimer patients compared to normal controls. Neuron 2013, 79, 1094–1108.