Misfolded tau protein and disease modifying pathways in transgenic rodent models of human tauopathies

Acta Neuropathologica

Volumn 118, Issue 1, 2009, Pages 71-86

  Zilka, Norbert ^a   Korenova, Miroslava ^a   Novak, Michal ^a,b  

^a INSTITUTE OF NEUROIMMUNOLOGY   (Slovakia)

^b Axon Neuroscience Forschungs und Entwicklungs GmbH   (Austria)

Author keywords

Alzheimer's disease; Disease pathways; Neurofibrillary degeneration; Tauopathies; Transgenic models

Indexed keywords

CD11B ANTIGEN; CD18 ANTIGEN; CD4 ANTIGEN; CD45 ANTIGEN; CD68 ANTIGEN; LYMPHOCYTE FUNCTION ASSOCIATED ANTIGEN 1; MICROTUBULE ASSOCIATED PROTEIN; TAU PROTEIN;

ALZHEIMER DISEASE; AMINO TERMINAL SEQUENCE; APOPTOSIS; CARBOXY TERMINAL SEQUENCE; CELL LEVEL; CELL MATURATION; DNA FRAGMENTATION; HISTOPATHOLOGY; HUMAN; IMMUNOREACTIVITY; MICROGLIA; MICROTUBULE ASSEMBLY; MISSENSE MUTATION; NERVE CELL NECROSIS; NERVE FIBER DEGENERATION; NEUROFIBRILLARY TANGLE; NEUROGENIC INFLAMMATION; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN GLYCOSYLATION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN STRUCTURE; REVIEW; TAUOPATHY; TRANSGENE; UBIQUITINATION; UPREGULATION;

ANIMALS; ANIMALS, GENETICALLY MODIFIED; CELL DEATH; DISEASE MODELS, ANIMAL; HUMANS; NERVE DEGENERATION; NEURONS; PHOSPHORYLATION; TAU PROTEINS; TAUOPATHIES;

EID: 67349087945     PISSN: 00016322     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00401-009-0499-y     Document Type: Review

References (177)

1. Allen B, Ingram E, Takao M et al (2002) Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22:9340-9351
2. Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci USA 98:6923-6928. doi: 10.1073/pnas.121119298
3. Alonso AC, Grundke-Iqbal I, Iqbal K (1996) Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med 2:783-787. doi: 10.1038/nm0796-783
4. Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K (1997) Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: Sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc Natl Acad Sci USA 94:298-303. doi: 10.1073/pnas.94.1.298
5. Alonso AD, Zaidi T, Novak M et al (2001) Interaction of tau isoforms with Alzheimer's disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein. J Biol Chem 276:37967-37973. doi: 10.1074/jbc.M006497200
6. Anderson AJ, Su JH, Cotman CW (1996) DNA damage and apoptosis in Alzheimer's disease: Colocalization with c-Jun immunoreactivity, relationship to brain area, and effect of postmortem delay. J Neurosci 16:1710-1719
7. Andorfer C, Kress Y, Espinoza M et al (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582-590. doi: 10.1046/j.1471-4159.2003.01879.x
8. Andorfer C, Acker CM, Kress Y et al (2005) Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25:5446-5454. doi: 10.1523/JNEUROSCI.4637-04.2005
9. Arendash GW, Lewis J, Leighty RE et al (2004) Multi-metric behavioral comparison of APPsw and P301L models for Alzheimer's disease: Linkage of poorer cognitive performance to tau pathology in forebrain. Brain Res 1012:29-41. doi: 10.1016/j.brainres.2004.02.081
10. Bancher C, Brunner C, Lassmann H et al (1989) Tau and ubiquitin immunoreactivity at different stages of formation of Alzheimer neurofibrillary tangles. Prog Clin Biol Res 317:837-848
11. Bellucci A, Westwood AJ, Ingram E et al (2004) Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein. Am J Pathol 165:1643-1652
12. Berger Z, Roder H, Hanna A et al (2007) Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27:3650-3662. doi: 10.1523/JNEUROSCI.0587-07.2007
13. Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101:1371-1378. doi: 10.1083/jcb.101.4.1371
14. Bobinski M, Wegiel J, Wisniewski HM et al (1996) Neurofibrillary pathology-correlation with hippocampal formation atrophy in Alzheimer disease. Neurobiol Aging 17:909-919
15. Boekhoorn K, Terwel D, Biemans B et al (2006) Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci 26:3514-3523. doi: 10.1523/JNEUROSCI.5425-05.2006
16. Bondareff W, Wischik CM, Novak M et al (1990) Molecular analysis of neurofibrillary degeneration in Alzheimer's disease. An immunohistochemical study. Am J Pathol 137:711-723
17. Braak H, Braak E (1997) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18:351-357. doi: 10.1016/ S0197-4580(97)00056-0
18. Brady RM, Zinkowski RP, Binder LI (1995) Presence of tau in isolated nuclei from human brain. Neurobiol Aging 16:479-486. doi: 10.1016/ 0197-4580(94)00170-6
19. Bramblett GT, Goedert M, Jakes R et al (1993) Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron 10:1089-1099. doi: 10.1016/0896-6273(93)90057-X
20. Brandt R, Lee G, Teplow DB, Shalloway D, Abdel-Ghany M (1994) Differential effect of phosphorylation and substrate modulation on tau's ability to promote microtubule growth and nucleation. J Biol Chem 269:11776-11782
21. Brandt R, Leger J, 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. doi: 10.1083/jcb.131.5.1327
22. Brion JP, Tremp G, Octave JN (1999) Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer's disease. Am J Pathol 154:255-270
23. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33:95-130. doi: 10.1016/ S0165-0173(00)00019-9
24. Bussiere T, Gold G, Kovari E et al (2003) Stereologic analysis of neurofibrillary tangle formation in prefrontal cortex area 9 in aging and Alzheimer's disease. Neuroscience 117:577-592. doi: 10.1016/ S0306-4522(02)00942-9
25. Cente M, Filipcik P, Pevalova M, Novak M (2006) Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy. Eur J NeuroSci 24:1085-1090. doi: 10.1111/ j.1460-9568.2006.04986.x
26. Cleveland DW, Hwo SY, Kirschner MW (1977) Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol 116:207-225. doi: 10.1016/ 0022-2836(77)90213-3
27. Cleveland DW, Hwo SY, Kirschner MW (1977) Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J Mol Biol 116:227-247. doi: 10.1016/0022-2836(77)90214-5
28. Cole AR, Noble W, van Aalten L et al (2007) Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression. J Neurochem 103:1132-1144. doi: 10.1111/ j.1471-4159.2007.04829.x
29. Collins RJ, Harmon BV, Gobe GC, Kerr JF (1992) Internucleosomal DNA cleavage should not be the sole criterion for identifying apoptosis. Int J Radiat Biol 61:451-453. doi: 10.1080/09553009214551201
30. Cras P, Kawai M, Siedlak S, Perry G (1991) Microglia are associated with the extracellular neurofibrillary tangles of Alzheimer disease. Brain Res 558:312-314. doi: 10.1016/0006-8993(91)90783-R
31. Crowther RA (1991) Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc Natl Acad Sci USA 88:2288-2292. doi: 10.1073/pnas.88.6.2288
32. Cullen KM, Halliday GM, Double KL et al (1997) Cell loss in the nucleus basalis is related to regional cortical atrophy in Alzheimer's disease. Neuroscience 78:641-652. doi: 10.1016/S0306-4522(96)00569-6
33. Dabir DV, Robinson MB, Swanson E et al (2006) Impaired glutamate transport in a mouse model of tau pathology in astrocytes. J Neurosci 26:644-654. doi: 10.1523/JNEUROSCI.3861-05.2006
34. David DC, Hauptmann S, Scherping I et al (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 280:23802-23814. doi: 10.1074/jbc.M500356200
35. Dawson HN, Cantillana V, Chen L, Vitek MP (2007) The tau N279K exon 10 splicing mutation recapitulates frontotemporal dementia and parkinsonism linked to chromosome 17 tauopathy in a mouse model. J Neurosci 27:9155-9168. doi: 10.1523/JNEUROSCI.5492-06.2007
36. Delobel P, Lavenir I, Ghetti B, Holzer M, Goedert M (2006) Cell-cycle markers in a transgenic mouse model of human tauopathy: Increased levels of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1. Am J Pathol 168:878-887. doi: 10.2353/ajpath.2006.050540
37. Delobel P, Lavenir I, Fraser G et al (2008) Analysis of tau phosphorylation and truncation in a mouse model of human tauopathy. Am J Pathol 172:123-131. doi: 10.2353/ajpath.2008.070627
38. Denk F, Wade-Martins R (2009) Knock-out and transgenic mouse models of tauopathies. Neurobiol Aging 30:1-13. doi: 10.1016/ j.neurobiolaging.2007.05.010
39. Deters N, Ittner LM, Gotz J (2008) Divergent phosphorylation pattern of tau in P301L tau transgenic mice. Eur J NeuroSci 28:137-147. doi: 10.1111/j.1460-9568.2008.06318.x
40. Dickson DW, Sinicropi S, Yen SH et al (1996) Glycation and microglial reaction in lesions of Alzheimer's disease. Neurobiol Aging 17:733-743. doi: 10.1016/0197-4580(96)00116-9
41. DiPatre PL, Gelman BB (1997) Microglial cell activation in aging and Alzheimer disease: Partial linkage with neurofibrillary tangle burden in the hippocampus. J Neuropathol Exp Neurol 56:143-149. doi: 10.1097/ 00005072-199702000-00004
42. Dou F, Netzer WJ, Tanemura K et al (2003) Chaperones increase association of tau protein with microtubules. Proc Natl Acad Sci USA 100:721-726. doi: 10.1073/pnas.242720499
43. Duff K, Knight H, Refolo LM et al (2000) Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol Dis 7:87-98. doi: 10.1006/nbdi.1999.0279
44. Duyckaerts C, Potier MC, Delatour B (2008) Alzheimer disease models and human neuropathology: Similarities and differences. Acta Neuropathol 115:5-38. doi: 10.1007/s00401-007-0312-8
45. Eckermann K, Mocanu MM, Khlistunova I et al (2007) The beta-propensity of tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. J Biol Chem 282:31755-31765. doi: 10.1074/ jbc.M705282200
46. Eckert A, Hauptmann S, Scherping I et al (2008) Soluble beta-amyloid leads to mitochondrial defects in amyloid precursor protein and tau transgenic mice. Neurodegener Dis 5:157-159. doi: 10.1159/000113689
47. Egashira N, Iwasaki K, Takashima A et al (2005) Altered depression-related behavior and neurochemical changes in serotonergic neurons in mutant R406W human tau transgenic mice. Brain Res 1059:7-12. doi: 10.1016/j.brainres.2005.08.004
48. Eriksen JL, Janus CG (2007) Plaques, tangles, and memory loss in mouse models of neurodegeneration. Behav Genet 37:79-100. doi: 10.1007/ s10519-006-9118-z
49. Forman MS, Lal D, Zhang B et al (2005) Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration. J Neurosci 25:3539-3550. doi: 10.1523/JNEUROSCI.0081-05.2005
50. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (1988) 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 85:4051-4055. doi: 10.1073/pnas.85.11.4051
51. Gomez-Isla T, Price JL, McKeel DW Jr et al (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci 16:4491-4500
52. Gomez-Isla T, Hollister R, West H et al (1997) Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann Neurol 41:17-24. doi: 10.1002/ana.410410106
53. Gotz J, Probst A, Spillantini MG et al (1995) Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J 14:1304-1313
54. Gotz J, Chen F, Barmettler R, Nitsch RM (2001) Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 276:529-534. doi: 10.1074/jbc.M006531200
55. Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491-1495. doi: 10.1126/science.1062097
56. Gotz J, Tolnay M, Barmettler R et al (2001) Oligodendroglial tau filament formation in transgenic mice expressing G272V tau. Eur J NeuroSci 13:2131-2140. doi: 10.1046/j.0953-816x.2001.01604.x
57. Greenberg SG, Davies P (1990) A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci USA 87:5827-5831. doi: 10.1073/ pnas.87.15.5827
58. Grundke-Iqbal I, Iqbal K, Quinlan M et al (1986) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261:6084-6089
59. Grundke-Iqbal I, Iqbal K, Tung YC et al (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913-4917. doi: 10.1073/pnas.83.13.4913
60. Halverson RA, Lewis J, Frausto S, Hutton M, Muma NA (2005) Tau protein is cross-linked by transglutaminase in P301L tau transgenic mice. J Neurosci 25:1226-1233. doi: 10.1523/JNEUROSCI.3263-04.2005
61. Hanes J, Zilka N, Bartkova M, Caletkova M, Dobrota D, Novak M (2009) Rat tau proteome consists of six tau isoforms: Implication for animal models of human tauopathies. J Neurochem 108:1167-1176
62. Hanger DP, Byers HL, Wray S et al (2007) Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem 282:23645-23654. doi: 10.1074/jbc.M703269200
63. Higuchi M, Ishihara T, Zhang B et al (2002) Transgenic mouse model of tauopathies with glial pathology and nervous system degeneration. Neuron 35:433-446. doi: 10.1016/S0896-6273(02)00789-4
64. Higuchi M, Zhang B, Forman MS et al (2005) Axonal degeneration induced by targeted expression of mutant human tau in oligodendrocytes of transgenic mice that model glial tauopathies. J Neurosci 25:9434-9443. doi: 10.1523/JNEUROSCI.2691-05.2005
65. Hong M, Zhukareva V, Vogelsberg-Ragaglia V et al (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282:1914-1917. doi: 10.1126/ science.282.5395.1914
66. Horiguchi T, Uryu K, Giasson BI et al (2003) Nitration of tau protein is linked to neurodegeneration in tauopathies. Am J Pathol 163:1021-1031
67. Hrnkova M, Zilka N, Minichova Z, Koson P, Novak M (2007) Neurodegeneration caused by expression of human truncated tau leads to progressive neurobehavioural impairment in transgenic rats. Brain Res 1130:206-213. doi: 10.1016/j.brainres.2006.10.085
68. Hua Q, He RQ (2002) Effect of phosphorylation and aggregation on tau binding to DNA. Protein Pept Lett 9:349-357. doi: 10.2174/ 0929866023408652
69. Ikeda M, Shoji M, Kawarai T et al (2005) Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice. Am J Pathol 166:521-531
70. Imamura K, Sawada M, Ozaki N et al (2001) Activation mechanism of brain microglia in patients with diffuse neurofibrillary tangles with calcification: A comparison with Alzheimer disease. Alzheimer Dis Assoc Disord 15:45-50. doi: 10.1097/00002093-200101000-00006
71. Iqbal K, Grundke-Iqbal I, Zaidi T et al (1986) Defective brain microtubule assembly in Alzheimer's disease. Lancet 2:421-426. doi: 10.1016/S0140-6736(86)92134-3
72. Iqbal K, Grundke-Iqbal I, Smith AJ et al (1989) Identification and localization of a tau peptide to paired helical filaments of Alzheimer disease. Proc Natl Acad Sci USA 86:5646-5650. doi: 10.1073/ pnas.86.14.5646
73. Ishihara T, Hong M, Zhang B et al (1999) Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24:751-762. doi: 10.1016/ S0896-6273(00)81127-7
74. Ishihara T, Zhang B, Higuchi M et al (2001) Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice. Am J Pathol 158:555-562
75. Ishizawa K, Dickson DW (2001) Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J Neuropathol Exp Neurol 60:647-657
76. Ittner LM, Fath T, Ke YD et al (2008) Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. Proc Natl Acad Sci USA 105:15997-16002. doi: 10.1073/pnas.0808084105
77. Jancsik V, Filliol D, Felter S, Rendon A (1989) Binding of microtubule-associated proteins (MAPs) to rat brain mitochondria: A comparative study of the binding of MAP2, its microtubule-binding and projection domains, and tau proteins. Cell Motil Cytoskeleton 14:372-381. doi: 10.1002/cm.970140307
78. Jellinger KA (1998) The neuropathological diagnosis of Alzheimer disease. J Neural Transm Suppl 53:97-118
79. Jellinger KA (2001) Cell death mechanisms in neurodegeneration. J Cell Mol Med 5:1-17. doi: 10.1111/j.1582-4934.2001.tb00134.x
80. Jellinger KA (2006) Challenges in neuronal apoptosis. Curr Alzheimer Res 3:377-391. doi: 10.2174/156720506778249434
81. Johnson GV, Stoothoff WH (2004) Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 117:5721-5729. doi: 10.1242/ jcs.01558
82. Katsuse O, Lin WL, Lewis J, Hutton ML, Dickson DW (2006) Neurofibrillary tangle-related synaptic alterations of spinal motor neurons of P301L tau transgenic mice. Neurosci Lett 409:95-99. doi: 10.1016/ j.neulet.2006.09.021
83. Kelleher I, Garwood C, Hanger DP, Anderton BH, Noble W (2007) Kinase activities increase during the development of tauopathy in htau mice. J Neurochem 103:2256-2267. doi: 10.1111/j.1471-4159.2007.04930.x
84. Kempf M, Clement A, Faissner A, Lee G, Brandt R (1996) Tau binds to the distal axon early in development of polarity in a microtubule- and microfilament-dependent manner. J Neurosci 16:5583-5592
85. Kidd M (1963) Paired helical filaments in electron microscopy of Alzheimer's disease. Nature 197:192-193. doi: 10.1038/197192b0
86. Kobayashi K, Hayashi M, Fukutani Y et al (1999) KP1 expression of ghost Pick bodies, amyloid P-positive astrocytes and selective nigral degeneration in early onset Picks disease. Clin Neuropathol 18:240-249
87. Kopke E, Tung YC, Shaikh S et al (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 268:24374-24384
88. Korenova M, Zilka N, Stozicka Z, Bugos O, Vanicky I, Novak M (2009) NeuroScale, the battery of behavioral tests with novel scoring system for phenotyping of transgenic rat model of tauopathy. J Neurosci Methods 177:108-114
89. Koson P, Zilka N, Kovac A et al (2008) Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load. Eur J NeuroSci 28:239-246. doi: 10.1111/j.1460-9568.2008.06329.x
90. Ksiezak-Reding H, Liu WK, Yen SH (1992) Phosphate analysis and dephosphorylation of modified tau associated with paired helical filaments. Brain Res 597:209-219. doi: 10.1016/0006-8993(92)91476-U
91. Lambourne SL, Sellers LA, Bush TG et al (2005) Increased tau phosphorylation on mitogen-activated protein kinase consensus sites and cognitive decline in transgenic models for Alzheimer's disease and FTDP-17: Evidence for distinct molecular processes underlying tau abnormalities. Mol Cell Biol 25:278-293. doi: 10.1128/ MCB.25.1.278-293.2005
92. Lambourne SL, Humby T, Isles AR et al (2007) Impairments in impulse control in mice transgenic for the human FTDP-17 tauV337M mutation are exacerbated by age. Hum Mol Genet 16:1708-1719. doi: 10.1093/hmg/ddm119
93. Ledesma MD, Bonay P, Colaco C, Avila J (1994) Analysis of microtubule-associated protein tau glycation in paired helical filaments. J Biol Chem 269:21614-21619
94. Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ (1991) A68: A major subunit of paired helical filaments and derivatized forms of normal tau. Science 251:675-678. doi: 10.1126/science.1899488
95. Lee VM, Kenyon TK, Trojanowski JQ (2005) Transgenic animal models of tauopathies. Biochim Biophys Acta 1739:251-259
96. Leroy K, Bretteville A, Schindowski K et al (2007) Early axonopathy preceding neurofibrillary tangles in mutant tau transgenic mice. Am J Pathol 171:976-992. doi: 10.2353/ajpath.2007.070345
97. Lewis J, McGowan E, Rockwood J et al (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402-405. doi: 10.1038/78078
98. Liazoghli D, Perreault S, Micheva KD, Desjardins M, Leclerc N (2005) Fragmentation of the golgi apparatus induced by the overexpression of wild-type and mutant human tau forms in neurons. Am J Pathol 166:1499-1514
99. Lim F, Hernandez F, Lucas JJ et al (2001) FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain. Mol Cell Neurosci 18:702-714. doi: 10.1006/mcne.2001.1051
100. Lin WL, Lewis J, Yen SH, Hutton M, Dickson DW (2003) Ultrastructural neuronal pathology in transgenic mice expressing mutant (P301L) human tau. J Neurocytol 32:1091-1105. doi: 10.1023/B:NEUR.0000021904.61387.95
101. Lin WL, Lewis J, Yen SH, Hutton M, Dickson DW (2003) Filamentous tau in oligodendrocytes and astrocytes of transgenic mice expressing the human tau isoform with the P301L mutation. Am J Pathol 162:213-218
102. Lin WL, Zehr C, Lewis J et al (2005) Progressive white matter pathology in the spinal cord of transgenic mice expressing mutant (P301L) human tau. J Neurocytol 34:397-410. doi: 10.1007/s11068-006-8726-0
103. Lucassen PJ, Chung WC, Kamphorst W, Swaab DF (1997) DNA damage distribution in the human brain as shown by in situ end labeling; area-specific differences in aging and Alzheimer disease in the absence of apoptotic morphology. J Neuropathol Exp Neurol 56:887-900. doi: 10.1097/00005072-199708000-00007
104. Lukiw WJ, Bazan NG (2000) Neuroinflammatory signaling upregulation in Alzheimer's disease. Neurochem Res 25:1173-1184. doi: 10.1023/ A:1007627725251
105. Mandelkow E, von Bergen M, Biernat J, Mandelkow EM (2007) Structural principles of tau and the paired helical filaments of Alzheimer's disease. Brain Pathol 17:83-90. doi: 10.1111/j.1750-3639.2007.00053.x
106. Mandelkow EM, Mandelkow E (1998) Tau in Alzheimer's disease. Trends Cell Biol 8:425-427. doi: 10.1016/S0962-8924(98)01368-3
107. McGeer PL, McGeer EG (1995) The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 21:195-218. doi: 10.1016/ 0165-0173(95)00011-9
108. McGeer PL, McGeer EG (2004) Inflammation and the degenerative diseases of aging. Ann N Y Acad Sci 1035:104-116. doi: 10.1196/annals.1332.007
109. Migheli A, Butler M, Brown K, Shelanski ML (1988) Light and electron microscope localization of the microtubule-associated tau protein in rat brain. J Neurosci 8:1846-1851
110. Mocanu MM, Nissen A, Eckermann K et al (2008) The potential for beta-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. J Neurosci 28:737-748. doi: 10.1523/JNEUROSCI.2824-07.2008
111. Mrak RE, Griffin WS (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26:349-354. doi: 10.1016/ j.neurobiolaging.2004.05.010
112. Mufson EJ, Ma SY, Cochran EJ et al (2000) Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer's disease. J Comp Neurol 427:19-30. doi: 10.1002/ 1096-9861(20001106)427:1<19::AID-CNE2>3.0.CO;2-A
113. Murakami T, Paitel E, Kawarabayashi T et al (2006) Cortical neuronal and glial pathology in TgTauP301L transgenic mice: Neuronal degeneration, memory disturbance, and phenotypic variation. Am J Pathol 169:1365-1375. doi: 10.2353/ajpath.2006.051250
114. Navarro P, Guerrero R, Gallego E et al (2008) Memory and exploratory impairment in mice that lack the Park-2 gene and that over-express the human FTDP-17 mutant Tau. Behav Brain Res 189:350-356. doi: 10.1016/ j.bbr.2008.01.017
115. Noble W, Planel E, Zehr C et al (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA 102:6990-6995. doi: 10.1073/ pnas.0500466102
116. Novak M, Wischik CM, Edwards P, Pannell R, Milstein C (1989) Characterisation of the first monoclonal antibody against the pronase resistant core of the Alzheimer PHF. Prog Clin Biol Res 317:755-761
117. Novak M, Jakes R, Edwards PC, Milstein C, Wischik CM (1991) Difference between the tau protein of Alzheimer paired helical filament core and normal tau revealed by epitope analysis of monoclonal antibodies 423 and 7.51. Proc Natl Acad Sci USA 88:5837-5841. doi: 10.1073/pnas.88.13.5837
118. Novak M, Kabat J, Wischik CM (1993) Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament. EMBO J 12:365-370
119. Novak M (1994) Truncated tau protein as a new marker for Alzheimer's disease. Acta Virol 38:173-189
120. Oka M, Katayama S, Watanabe C et al (1998) Argyrophilic structures stimulate glial reactions in neurofibrillary tangles and senile plaques. Neurol Res 20:121-126
121. Overmyer M, Helisalmi S, Soininen H et al (1999) Reactive microglia in aging and dementia: An immunohistochemical study of postmortem human brain tissue. Acta Neuropathol 97:383-392. doi: 10.1007/s004010051002
122. Paulus W, Bancher C, Jellinger K (1993) Microglial reaction in Pick's disease. Neurosci Lett 161:89-92. doi: 10.1016/0304-3940(93)90147-D
123. Pennanen L, Welzl H, D'Adamo P, Nitsch RM, Gotz J (2004) Accelerated extinction of conditioned taste aversion in P301L tau transgenic mice. Neurobiol Dis 15:500-509. doi: 10.1016/j.nbd.2003.11.020
124. Pennanen L, Wolfer DP, Nitsch RM, Gotz J (2006) Impaired spatial reference memory and increased exploratory behavior in P301L tau transgenic mice. Genes Brain Behav 5:369-379. doi: 10.1111/ j.1601-183X.2005.00165.x
125. Perlmutter LS, Scott SA, Barron E, Chui HC (1992) MHC class II-positive microglia in human brain: Association with Alzheimer lesions. J Neurosci Res 33:549-558. doi: 10.1002/jnr.490330407
126. Probst A, Gotz J, Wiederhold KH et al (2000) Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol 99:469-481. doi: 10.1007/s004010051148
127. Ramalho RM, Viana RJ, Castro RE et al (2008) Apoptosis in transgenic mice expressing the P301L mutated form of human tau. Mol Med 14:309-317. doi: 10.2119/2007-00133.Ramalho
128. Ramsden M, Kotilinek L, Forster C et al (2005) Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci 25:10637-10647. doi: 10.1523/JNEUROSCI.3279-05.2005
129. Reynolds CH, Garwood CJ, Wray S et al (2008) Phosphorylation regulates tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cgamma1, Grb2, and Src family kinases. J Biol Chem 283:18177-18186. doi: 10.1074/jbc.M709715200
130. Rohn TT, Vyas V, Hernandez-Estrada T et al (2008) Lack of pathology in a triple transgenic mouse model of Alzheimer's disease after overexpression of the anti-apoptotic protein Bcl-2. J Neurosci 28:3051-3059. doi: 10.1523/JNEUROSCI.5620-07.2008
131. Rosenmann H, Grigoriadis N, Eldar-Levy H et al (2008) A novel transgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics. Exp Neurol 212:71-84. doi: 10.1016/ j.expneurol.2008.03.007
132. Rossler M, Zarski R, Bohl J, Ohm TG (2002) Stage-dependent and sector-specific neuronal loss in hippocampus during Alzheimer's disease. Acta Neuropathol 103:363-369. doi: 10.1007/s00401-001-0475-7
133. Sadik G, Tanaka T, Kato K et al (2009) Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: Implications for the mechanism of tau aggregation. J Neurochem 108:33-43. doi: 10.1111/ j.1471-4159.2008.05716.x
134. Sahara N, Lewis J, DeTure M et al (2002) Assembly of tau in transgenic animals expressing P301L tau: Alteration of phosphorylation and solubility. J Neurochem 83:1498-1508. doi: 10.1046/ j.1471-4159.2002.01241.x
135. Santacruz K, Lewis J, Spires T et al (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476-481. doi: 10.1126/science.1113694
136. Sasaki A, Kawarabayashi T, Murakami T et al (2008) Microglial activation in brain lesions with tau deposits: Comparison of human tauopathies and tau transgenic mice TgTauP301L. Brain Res 1214:159-168. doi: 10.1016/ j.brainres.2008.02.084
137. Sengupta A, Kabat J, Novak M et al (1998) Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys 357:299-309. doi: 10.1006/ abbi.1998.0813
138. Sengupta A, Novak M, Grundke-Iqbal I, Iqbal K (2006) Regulation of phosphorylation of tau by cyclin-dependent kinase 5 and glycogen synthase kinase-3 at substrate level. FEBS Lett 580:5925-5933. doi: 10.1016/j.febslet.2006.09.060
139. Sheffield LG, Marquis JG, Berman NE (2000) Regional distribution of cortical microglia parallels that of neurofibrillary tangles in Alzheimers disease. Neurosci Lett 285:165-168. doi: 10.1016/ S0304-3940(00)01037-5
140. Sheng JG, Mrak RE, Griffin WS (1997) Glial-neuronal interactions in Alzheimer disease: Progressive association of IL-1alpha + microglia and S100beta + astrocytes with neurofibrillary tangle stages. J Neuropathol Exp Neurol 56:285-290. doi: 10.1097/00005072-199703000-00007
141. Schindowski K, Bretteville A, Leroy K et al (2006) Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169:599-616. doi: 10.2353/ajpath.2006.060002
142. Schindowski K, Belarbi K, Bretteville A, Ando K, Buee L (2008) Neurogenesis and cell cycle-reactivated neuronal death during pathogenic tau aggregation. Genes Brain Behav 7(Suppl 1):92-100
143. Schneider A, Biernat J, von Bergen M, Mandelkow E, Mandelkow EM (1999) Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 38:3549-3558. doi: 10.1021/bi981874p
144. Schonheit B, Zarski R, Ohm TG (2004) Spatial and temporal relationships between plaques and tangles in Alzheimer-pathology. Neurobiol Aging 25:697-711. doi: 10.1016/j.neurobiolaging.2003.09.009
145. Schwab C, Steele JC, McGeer PL (1996) Neurofibrillary tangles of Guam parkinson-dementia are associated with reactive microglia and complement proteins. Brain Res 707:196-205. doi: 10.1016/0006-8993(95)01257-5
146. Simic G, Kostovic I, Winblad B, Bogdanovic N (1997) Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer's disease. J Comp Neurol 379:482-494. doi: 10.1002/ (SICI)1096-9861(19970324)379:4<482::AID-CNE2>3.0.CO;2-Z
147. Skrabana R, Sevcik J, Novak M (2006) Intrinsically disordered proteins in the neurodegenerative processes: Formation of tau protein paired helical filaments and their analysis. Cell Mol Neurobiol 26:1085-1097. doi: 10.1007/s10571-006-9083-3
148. Skrabana R, Skrabanova M, Csokova N, Sevcik J, Novak M (2006) Intrinsically disordered tau protein in Alzheimer's tangles: A coincidence or a rule? Bratisl Lek Listy (Tlacene Vyd) 107:354-358
149. Spires-Jones TL, de Calignon A, Matsui T et al (2008) In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons. J Neurosci 28:862-867. doi: 10.1523/ JNEUROSCI.3072-08.2008
150. Spires TL, Orne JD, SantaCruz K et al (2006) Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol 168:1598-1607. doi: 10.2353/ ajpath.2006.050840
151. Spittaels K, Van den Haute C, Van Dorpe J et al (1999) Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol 155:2153-2165
152. Stadelmann C, Bruck W, Bancher C, Jellinger K, Lassmann H (1998) Alzheimer disease: DNA fragmentation indicates increased neuronal vulnerability, but not apoptosis. J Neuropathol Exp Neurol 57:456-464
153. Straiko MM, Coolen LM, Zemlan FP, Gudelsky GA (2007) The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain. Neuroscience 144:223-231. doi: 10.1016/ j.neuroscience.2006.08.073
154. Tanemura K, Akagi T, Murayama M et al (2001) Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau. Neurobiol Dis 8:1036-1045. doi: 10.1006/nbdi.2001.0439
155. Tanemura K, Murayama M, Akagi T et al (2002) Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J Neurosci 22:133-141
156. Taniguchi T, Doe N, Matsuyama S et al (2005) Transgenic mice expressing mutant (N279K) human tau show mutation dependent cognitive deficits without neurofibrillary tangle formation. FEBS Lett 579:5704-5712. doi: 10.1016/j.febslet.2005.01.039
157. Tatebayashi Y, Miyasaka T, Chui DH et al (2002) Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc Natl Acad Sci USA 99:13896-13901. doi: 10.1073/ pnas.202205599
158. Terwel D, Lasrado R, Snauwaert J et al (2005) Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice. J Biol Chem 280:3963-3973. doi: 10.1074/jbc.M409876200
159. Tucholski J, Kuret J, Johnson GV (1999) Tau is modified by tissue transglutaminase in situ: Possible functional and metabolic effects of polyamination. J Neurochem 73:1871-1880
160. Vega IE, Cui L, Propst JA et al (2005) Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates. Brain Res Mol Brain Res 138:135-144. doi: 10.1016/j.molbrainres.2005.04.015
161. Vega IE, Traverso EE, Ferrer-Acosta Y et al (2008) A novel calcium-binding protein is associated with tau proteins in tauopathy. J Neurochem 106:96-106. doi: 10.1111/j.1471-4159.2008.05339.x
162. Velasco A, Fraser G, Delobel P, et al (2008) Detection of filamentous tau inclusions by the fluorescent Congo red derivative FSB. FEBS Lett 582:901-906.
163. Vereecken TH, Vogels OJ, Nieuwenhuys R (1994) Neuron loss and shrinkage in the amygdala in Alzheimer's disease. Neurobiol Aging 15:45-54. doi: 10.1016/0197-4580(94)90143-0
164. Vitek MP, Bhattacharya K, Glendening JM et al (1994) Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci USA 91:4766-4770. doi: 10.1073/pnas.91.11.4766
165. von Gunten A, Kovari E, Bussiere T et al (2006) Cognitive impact of neuronal pathology in the entorhinal cortex and CA1 field in Alzheimer's disease. Neurobiol Aging 27:270-277. doi: 10.1016/ j.neurobiolaging.2005.02.008
166. Wang JZ, Grundke-Iqbal I, Iqbal K (1996) Glycosylation of microtubule-associated protein tau: An abnormal posttranslational modification in Alzheimer's disease. Nat Med 2:871-875. doi: 10.1038/ nm0896-871
167. Wang Y, Loomis PA, Zinkowski RP, Binder LI (1993) A novel tau transcript in cultured human neuroblastoma cells expressing nuclear tau. J Cell Biol 121:257-267. doi: 10.1083/jcb.121.2.257
168. West MJ, Coleman PD, Flood DG, Troncoso JC (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet 344:769-772. doi: 10.1016/S0140-6736(94)92338-8
169. West MJ, Kawas CH, Stewart WF, Rudow GL, Troncoso JC (2004) Hippocampal neurons in pre-clinical Alzheimer's disease. Neurobiol Aging 25:1205-1212. doi: 10.1016/j.neurobiolaging.2003.12.005
170. Wischik CM, Novak M, Edwards PC et al (1988) Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 85:4884-4888. doi: 10.1073/pnas.85.13.4884
171. Wischik CM, Novak M, Thogersen HC et al (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 85:4506-4510. doi: 10.1073/ pnas.85.12.4506
172. Yan SD, Chen X, Schmidt AM et al (1994) Glycated tau protein in Alzheimer disease: A mechanism for induction of oxidant stress. Proc Natl Acad Sci USA 91:7787-7791. doi: 10.1073/pnas.91.16.7787
173. Yoshiyama Y, Higuchi M, Zhang B et al (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337-351. doi: 10.1016/j.neuron.2007.01.010
174. Zehr C, Lewis J, McGowan E et al (2004) Apoptosis in oligodendrocytes is associated with axonal degeneration in P301L tau mice. Neurobiol Dis 15:553-562. doi: 10.1016/j.nbd.2003.12.011
175. Zhang B, Higuchi M, Yoshiyama Y et al (2004) Retarded axonal transport of R406W mutant tau in transgenic mice with a neurodegenerative tauopathy. J Neurosci 24:4657-4667. doi: 10.1523/JNEUROSCI.0797-04.2004
176. Zilka N, Filipcik P, Koson P et al (2006) Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett 580:3582-3588. doi: 10.1016/j.febslet.2006.05.029
177. Zilka N, Stozicka Z, Kovac A, et al (2009) Human misfolded truncated tau protein promotes activation of microglia and leukocyte infiltration in the transgenic rat model of tauopathy. J Neuroinflammation (in press)