Genetically modified mice models for Alzheimer's disease

Current Topics in Medicinal Chemistry

Volumn 6, Issue 6, 2006, Pages 609-627

  Sankaranarayanan, Sethu ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Abeta; Alzheimer's; Amyloid; APP; Intraneuronal; Mutation; Neurodegeneration; Oligomer; Tau; Transgenic

Indexed keywords

AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; AMYLOID PRECURSOR PROTEIN; BETA SECRETASE; CYCLIN DEPENDENT KINASE 5; DNA; GAMMA SECRETASE; ISOPROTEIN; NERVE GROWTH FACTOR; OLIGOMER; PRESENILIN 1; PRESENILIN 2; PROTEIN P25; TAU PROTEIN;

ALZHEIMER DISEASE; ANIMAL BEHAVIOR; CHROMOSOME 1; CHROMOSOME 14; CHROMOSOME 21; DISEASE MODEL; DNA MODIFICATION; GENE MUTATION; GENETIC LINKAGE; HYPOTHESIS; MISSENSE MUTATION; MOUSE; NERVE DEGENERATION; NEUROFIBRILLARY TANGLE; NEUROPATHOLOGY; NEUROTOXICITY; NONHUMAN; PATHOGENESIS; PATHOPHYSIOLOGY; PREDICTION; PROTEIN PROCESSING; PROTEIN SYNTHESIS; REVIEW; TAUOPATHY; TRANSGENIC MOUSE; TREATMENT OUTCOME;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN; AMYLOID BETA-PROTEIN PRECURSOR; ANIMALS; DISEASE MODELS, ANIMAL; MICE; MICE, TRANSGENIC; NERVE GROWTH FACTOR; NERVE TISSUE PROTEINS; TAU PROTEINS;

EID: 33646199606     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802606776743020     Document Type: Review

References (238)

1. Berg, L.; Morris, J. C.;Terry, R. D.; Katzman, R.; Bick, K. L. Diagnosis. In Alzheimer Disease Eds.; Raven Press: New York, 1994; pp. 197-229.
2. Strittmatter, W. J.; Saunders, A. M.; Schmechel, D.; Pericak-Vance, M.; Enghild, J.; Salvesen, G. S.; Roses, A. D. Apolipoprotein E: High avidity binding to ß-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. USA 1993, 90 1977-1981
3. Strittmatter, W. J.; Roses, A. D. Apolipoprotein E and Alzheimer's disease. Annu. Rev. Neurosci. 1996, 19, 53-77.
4. Bertram, L.; Blacker, D.; Mullin, K.; Keeney, D.; Jones, J.; Basu, S.; Yhu, S.; McInnis, M. G.; Go, R. C.; Vekrellis, K.; Selkoe, D. J.; Saunders, A. J.; Tanzi, R. E. Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science 2000, 290, 2302-2303.
5. Ertekin-Taner, N.; Graff-Radford, N.; Younkin, L. H.; Eckman, C.; Baker, M.; Adamson, J.; Ronald, J.; Blangero, J.; Hutton, M.; Younkin, S. G. Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Science 2000, 290, 2303-2304.
6. Blacker, D.; Bertram, L.; Saunders, A. J.; Moscarillo, T. J.; Albert, M. S.; Wiener, H.; Perry, R. T.; Collins, J. S.; Harrell, L. E.; Go, R. C.; Mahoney, A.; Beaty, T.; Fallin, M. D.; Avramopoulos, D.; Chase, G. A.; Folstein, M. F.; McInnis, M. G.; Bassett, S. S.; Doheny, K. J.; Pugh, E. W.; Tanzi, R. E. NIMH Genetics Initiative Alzheimer's Disease Study Group. Results of a high-resolution genome screen of 437 Alzheimer's disease families. Hum. Mol. Genet. 2003, 12, 23-32.
7. Ertekin-Taner, N.; Ronald, J.; Asahara, H.; Younkin, L.; Hella, M.; Jain, S.; Gnida, E.; Younkin, S.; Fadale, D.; Ohyagi, Y.; Singleton, A.; Scanlin, L.; de Andrade, M.; Petersen, R.; Graff-Radford, N.; Hutton, M.; Younkin, S. Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Hum. Mol. Genet 2003, 12,3133-3143.
8. Ertekin-Taner, N.; Ronald, J.; Feuk, L.; Prince, J.; Tucker, M.; Younkin, L.; Hella, M.; Jain, S.; Hackett, A.; Scanlin, L.; Kelly, J.; Kihiko-Ehman, M.; Neltner, M.; Hersh, L.; Kindy, M.; Markesbery, W.; Hutton, M.; de Andrade, M.; Petersen, RC.; Graff-Radford, N.; Estus, S.; Brookes, A. J.; Younkin, S. G. Elevated amyloid beta protein (Abeta42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene. Hum. Mol. Genet. 2005, 14, 447-460.
9. Petersen, R. C.; Smith, G. E.; Waring, S. C.; Ivnik, R. J.; Tangalos, E. G.; Kokmen, E. Mild cognitive impairment: clinical characterization and outcome. Arch. Neurol. 1999, 56, 303-308.
10. Whitehouse, P. J.; Price, D. L.; Struble, R.; Clarke, A.; Coyle, J.; Delong, M. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 1982, 215, 1237-1239.
11. Hyman, B. T.; Van Hoesen, G. W.; Damasio, A. R.; Barnes, C. L. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science 1984, 225, 1168-1170.
12. Arnold, S. E.; Hyman, B. T.; Flory, J.; Damasio, A. R.; Van Hoesen, G. W. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb. Cortex 1991, 1, 103-116.
13. Terry, R. D.; Masliah, E.; Hansen, L. A. The neuropathology of Alzheimer disease and the structural basis of its cognitive alterations. In Alzheimer Disease Eds.; Lippincott, Williams and Wilkins; Philadelphia, 1999; pp. 187-206.
14. Braak, H.; Braak, E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathologica 199l, 82, 239-259.
15. Terry, R. D.; Masliah, E.; Salmon, D. P.; Butters, N.; DeTeresa, R.; Hill, R. D.; Hansen, L. A.; Katzman, R. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 1991, 30, 572-580.
16. Crowther, R. A.; Wischik, C. M. Image reconstruction of the Alzheimer paired helical filament. EMBO J. 1985, 4, 3661-3665.
17. Wischik, C. M.; Crowther, R. A.; Stewart, M.; Subunit structure of paired helical filaments in Alzheimer's disease. J. Cell Biol. 1985, 100, 1905-1912.
18. Grunke-Iqbal, I.; lqbal, 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.
19. Goedert, M.; Spillantini, M. G.; Cairns, N. J.; Crowther, R. A. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms Neuron 1992, 8, 159-162.
20. Gomez-Isla, T.; Price, J. L.; McKeel, D. W.; Morris, J. C.; Growden, J. H.; Hyman, B. T. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J. Neurosci. 1996, 16, 4491-4500.
21. Morris, J. C.; Price, A. L. Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer's disease. J. Mol. Neurosci. 2001, 17, 101-118.
22. DeKosky, S. T.; Scheff, S. W. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann. Neurol. 1990, 27, 457-464.
23. Terry, R. D.; Masliah, E.; Salmon, D. P.; Butters, N.; DeTeresa, R.; Hill, R.; Hansen, L. A.; Katzman, R. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 1991, 30, 572-580.
24. Coleman, P. D.; Yao, P. J. Synaptic slaughter in Alzheimer's disease Neurobiol. Aging 2003, 24, 1023-1027.
25. Scheff, S. W.; Price, D. A.; Schmitt, F. A.; Mufson, E. J. Hippocampal synaptic loss in e arly Alzheimer's disease and mild cognitive impairment. Neurobiol. Aging 2005 [Epub ahead of print].
26. Davies, C. A.; Mann, D. M.; Sumpter, P. Q.; Yates, P. O. A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease. J. Neurol. Sci. 1987, 78, 151-164.
27. Bertoni-Freddari, C.; Fattoretti, P.; Solazzi, M.; Giorgetti, B.; Di Stefano, G.; Casoli, T.; Meier-Ruge, W. Neuronal death versus synaptic pathology in Alzheimer's disease. Ann. N. Y. Acad. Sci. 2003, 1010, 635-638
28. McLean, C. A.; Cherny, R. A.; Fraser, F. W.; Fuller, S. J.; Smith, M. J.; Beyreuther, K.; Bush, A, I.; Masters, C. L. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol. 1999, 46, 860-866.
29. Naslund, J.; Haroutunian, V.; Mohs, R.; Davis, K. L.; Davies, P.; Greengard, P.; Buxbaum, J. D. Correlation between elevated levels of amyloid beta peptide in the brain and cognitive decline. JAMA 2000, 283, 1571-1577,
30. Lue, L. F.; Kuo, Y. M.; Roher, A. E.; Brachova, L.; Shen, Y.; Sue, L.; Beach, T.; Kurth, J. H.; Rydel, R. E.; Rogers, J. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am. J. Pathol. 1999, 155, 853-862.
31. Chapman, P. F.; Falinska, A. M.; Knevett, S. G.; Ramsay, M. F. Genes, models and Alzheimer's disease. Trends Genet. 2001, 17, 254-261.
32. Higgins, G. A.; Jacobsen, H. Transgenic mouse models of Alzheimer's disease: phenotype and application. Behav. Pharm. 2003, 14, 419-438.
33. Morgan, D. Learning and Memory Deficits in APP Transgenic mouse models of Amyloid deposition. Neurochem. Res. 2003, 28, 1029-1034.
34. Gotz, J.; Schild, A.; Hoerndli, F.; Pennanen, L. Amyloid-induced neurofibrillary tangle formation in Alzheimer's disease: insight from transgenic mouse and tissue-culture models. Int. J. Dev. Neurosci. 2004, 22, 453-465
35. Tanzi, R. E.; Bertram, L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 2005, 120, 545-555.
36. Glenner, G. G.; Wong, C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 1984, 120, 885-890.
37. Masters, C. L.; Simms, G.; Weinman, N. A.; Multhaup, G.; McDonald, B. L.; Beyreuther, K. Amyloid plaque core protein in Alzheimer's disease and Down's syndrome. Proc. Natl. Acad. Sci. U. S. A. 1985, 82, 4245-4249.
38. Kang, J.; Lemaire, H. G.; Unterbeck, A.; Salbaum, J.; Masters, C.; Grzeschik, K. H.; Multhaup, G.; Beyreuther, K.; Muller-Hill, B. The precursor of Alzheimer's disease amyloid A4 resembles a cell-surface receptor. Nature 1987, 325, 733-736.
39. Tanzi, R. E.; Gusella, J. F.; Watkins, P. C.; Bruns, G. A. P.; St George-Hyslop, P. H.; Van Keuren, M. L.; Patterson, D.; Pagan, S.; Kurnit, D. M.; Neve, R. L. Amyloid β- protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus, Science 1987,235, 880-888.
40. Tanaka, S.; Shiojiri, S.; Takahashi, Y.; Kitaguchi, N.; Ito, H.; Kameyama, M.; Kimura, J.; Nakamura, S.; Ueda; K. Tissue-specific expression of three types of β-protein precursor mRNA: Enhancement of protease inhibitor-harboring types in Alzheimer's disease brains. Biochem. Biophys. Res. Comm. 1989, 165, 1406-1414,
41. Golde, T.; Estus, S.; Usiak, M.; Youngkin, L.; Youngkin, S. Expression of beta-amyloid protein precursor mRNAs: recognition of a novel alternatively spliced form and quantitation in Alzheimer's disease using PCR. Neuron 1990, 4, 253-267.
42. Koo, E. H.; Sisodia, S. S.; Archer, D. R.; Martin, L. J.; Weidemann, A.; Beyreuther, K.; Fischer, P.; Masters, C. L.; Price, D. L. Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc. Natl Acad. Sci U. S. A. 1990, 87, 1561-1565.
43. Buxbaum, J. D.; Thinkaran, G.; Koliatsos, V. Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path. J. Neurosci. 1998, 18, 9629-9637.
44. Oliver, C.; Holland, A. J. Down's syndrome and Alzheimer's disease: a review. Psychol. Med. 1980, 16, 307-322.
45. van Broeckhoven, C.; Haan, J.; Bakker, E.; Hardy, J.; van Hul, W.; Wehnert, A.; Vegter- van-der Vlis, M.; Roos, R. Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science 1990, 248, 1120-1122.
46. Luyendijk, W.; Bots, G.; Vegter-van-der Vlis, M.; Went, L.; Frangione, B. Hereditary cerebral hemorrhage caused by cortical amyloid angiopathy. J. Neurol. Sci. 1988, 85, 267-280.
47. Levy, E.; Carman, M.; Fernandez-Madrid, I.; Power, M.; Lieberburg, I.; van Duinen, S.; Bots, G.; Luyendijk, W.; Frangione, B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 1990, 248, 1124-1126.
48. Crawford, F.; Goate, A. Alzheimer's disease untangled. Bioessays 1992, 14, 727-734.
49. Goate, A.; Chartier-Harlin, M. C.; Mullan, M.; Brown, J.; Crawford, F.; Fidani, L.; Giuffra, L.; Haynes, A.; Irving, N.; James, L.; Mant, R.; Newton, P.; Rooke, K.; Roques, P.; Talbot, C.; Pericak-Vance, M.; Roses, A.; Williamson, R.; Rossor, M.; Owen, M.; Hardy, J. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease, Nature 1991, 349, 704-706.
50. Chartier-Harlin, M. C.; Crawford, F.; Houlden, H.; Warren, A.; Hughes, D.; Fidani, L.; Goate, A.; Rossor, M.; Roques, P.; Hardy, J.; Mullan, M. Early-onset Alzheimer's disease caused by mutation at codon 717 of the β-amyloid precursor protein gene. Nature 1991, 353, 844-846
51. Murrell, J.; Farlow, M.; Ghetti, B.; Benson, M. A mutation in the Amyloid Precursor Protein associated with hereditary Alzheimer's disease. Science 1991, 254, 97-99.
52. Mullan, M.; Crawford, F.; Axelman, K.; Houlden, H.; Lilius, L.; Winblad, B.; Lannfelt, L. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N- terminus of beta-amyloid. Nat. Genet. 1992, 1, 345-347.
53. Citron, M.; Oltersdorf, T.; Haass, C.; McConlogue, L.; Hung, A. Y.; Seubert, P.; Vigo- Pelfrey, C.; Lieberburg, I.; Selkoe, D. J. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 1992, 360, 672- 674.
54. Suzuki, N.; Cheung, T. T.; Cai, X. D.; Odaka, A.; Otvos, L. Jr.; Eckman, C.; Golde, T. E.; Younkin, S. G. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 1994, 264, 1336-1340.
55. Sherrington, R.; Rogaev, E. I.; Liang, Y.; Rogaeva, E. A.; Levesque, G.; Ikeda, M.; Chi, H.; Lin, C.; Li, G., Holman, K.; Tsuda, T.; Mar, L.; Foncin, J.-F.; Bruni, A. C.; Montesi, M. P.; Sorbi, S.; Rainero, I.; Pinessi, L.; Nee, L.; Chumakov, I.; Pollen, D. A.; Roses, A. D.; Fraser, P. E.; Rommens, J. M.; St George-Hyslop, P. H. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995, 375, 754-760.
56. Levy-Labad, E.; Wasco, W.; Poorkaj, P.; Romano, D. M.; Oshima, J.; Pettingell, H.; Yu, C.; Jondro, P. D.; Schmidt, S. D.; Wang, K.; Crowley, A. C.; Fu, Y.-H.; Guenette, S. Y.; Galas, D.; Nemens, E.; Wijsman, E. M.; Bird, T. D.; Schellenberg, G. D.; Tanzi, R. E. Candidate gene for the chromosome l familial Alzheimer's disease locus. Science 1995, 269, 973-977.
57. Rogaev, E. I.; Sherrington, R.; Rogaeva, E. A.; Levesque, G.; Ikeda, M.; Liang, Y.; Chi, H.; Lin, C.; Holamn, K.; Tsuda, T.; Mar, L.; Sorbi, S.; Nacmias, B.; Piacentini, S.; Amaducci, L.; Chumakov, L; Cohen, D.; Larinfelt, L.; Fraser, P. E.; Rommens, J. M.; St George-Hyslop, P. H. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 1995, 376, 775-778.
58. Van Broeckhoven, C. Presenilins and Alzheimer disease. Nat. Genet. 1995, 11, 230-232.
59. Selkoe, D. J.; Podlisny, M. B. Deciphering the genetic basis of Alzheimer's disease. Annu. Rev. Genomics Hum. Genet 2002, 3, 67-99.
60. Li, Y. M.; Xu, M.; Lai, M. T.; Huang, Q.; Castro, J. L.; DiMuzio- Mower, J. Harrison, T.; Lellis, C.; Nadin, A.; Neduvelil, J. G.; Register, R. B.; Sardana, M. K.; Shearman, M. S.; Smith, A.L.; Shi, X. P.; Yin, K. C.; Shafer, J. A.; Gardell, S. J. Photoactivated gamma- secretase inhibitors directed to the active site covalently label presenilin 1. Nature 2000, 405, 689-694.
61. De Strooper, B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 2003, 38, 9-12.
62. De Strooper, B.; Saftig, P.; Craessaerts, K.; Vanderstichele, H.; Guhde, G.; Annaert, W.; Von Figura, K.; Van Leuven, F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998, 391, 387-390.
63. Mehta, N. D.; Refolo, L. M.; Eckman, C.; Sanders, S.; Yager, D.; Perez-Tur, J.; Younkin, S.; Duff, K.; Hardy, J.; Hutton, M. Increased Abeta42(43) from cell lines expressing presenilin 1 mutations. Ann. NeuroL 1998, 43, 256-258.
64. Xia, W.; Zhang, J.; Kholodenko, D.; Citron, M.; Podlisny, M. B.; Teplow, D. B.; Haass, C.; Seubert, P.; Koo, E. H.; Selkoe, D. J. Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins. J. Biol. Chem. 1997, 272, 7977-7982.
65. Hussain, I.; Powell, D.; Howlett, D. R.; Tew, D. G.; Meek, T. D.; Chapman, C.; Gloger, I. S.; Murphy, K. E.; Southan, C. D.; Ryan, D. M.; Smith, T. S.; Simmons, D. L.; Walsh, F. S.; Dingwall, C.; Christie, G. Identification of a novel aspartic protease (Asp 2) as beta- secretase. Mol. Cell Neurosci. 1999, 14, 419- 427.
66. Sinha, S.; Anderson, J. P.; Barbour, R.; Basi, G. S.; Caccavello, R.; Davis, D.; Doan, M.; Dovey, H. F.; Frigon, N.; Hong, J.; Jacobson- Croak, K.; Jewett, N.; Keim, P.; Knops, J.; Lieberburg, I; Power, M.; Tan, H.; Tatsuno, G.; Tung, J.; Schenk, D.; Seubert, P.; Suomensaari, S. M.; Wang, S.; Walker, D.; Zhao, J.; McConlogue, L.; John, V. Purification and cloning of amyloid precursor protein betasecretase from human brain. Nature 1999,402, 537-540.
67. Vassar, R.; Bennett, B. D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E. A.; Denis, P.; Teplow, D. B.; Ross, S.; Amarante, P.; Loeloff, R.; Luo, Y.; Fisher, S.; Fuller, J.; Edenson, S.; Lile, J.; Jarosinski, M. A.; Biere, A. L.; Curran, E.; Burgess, T.; Louis, J. C.; Collins, F.; Treanor, J.; Rogers, G.; Citron, M. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999, 286, 735- 741.
68. Yan, R.; Bienkowski, M. J.; Shuck, M. E.; Miao, H.; Tory, M. C.; Pauley, A. M.; Brashier, J. R.; Stratman, N. C.; Mathews, W. R.; Buhl, A. E.; Carter, D. B.; Tomasselli, A. G.; Parodi, L.A.; Heinrikson, R.L.; Gurney, M.E. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 1999, 402, 533-537.
69. Cai, H.; Wang, Y.; McCarthy, D.; Wen, H.; Borchelt, D. R.; Price, D. L.; Wong, P. C. BACEI is the major beta-secretase for generation of Abeta peptides by neurons. Nat. Neurosci. 2001, 4, 233-234.
70. Luo, Y.; Bolon, B.; Damore, M. A.; Fitzpatrick, D.; Liu, H.; Zhang, J.; Yan, Q.; Vassar, R.; Citron, M. BACE1 (beta-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time. Neurobiol. Dis. 2003, 14, 81-88.
71. Roberds, S. L.; Anderson, J.; Basi, G.; Bienkowski, M. J.; Branstetter, D. G.; Chen, K S.; Freedman', S. B.; Frigon, N. L.; Games, D.; Hu, K.; Johnson-Wood, K.; Kappemnan, K. E.; Kawabe, T. T.; Kola, L; Kuehn, R.; Lee, M.; Liu, W.; Motter, R.; Nichols, N. F.; Power, M.; Robertson, D. W.; Schenk, D.; Schoor, M.; Shopp, G. M.; Shuck, M.E; Sinha, S.; Svensson, K. A.; Tatsuno, G.; Tintrup, H.; Wijsman, J.; Wright, S.; McConlogue, L. BACE knockout mice are healthy despite lacking the primary betasecretase activity in brain: implications for Alzheimer's disease therapeutics. Hum. Mol. Genet. 2001, 10, 1317-1324.
72. Bodendorf, U.; Danner, S.; Fischer, F.; Stefani, M.; Sturchler-Pierrat, C.; Wiederhold, K. H.; Stairfenbiel, M.; Paganetti, P. Expression of human beta-secretase in the mouse brain increases the steady-state level of beta-amyloid. J. Neurochem. 2002, 80, 799-806.
73. Mohajeri, M. H.; Saini K. D.; Nitsch, R. M. Transgenic BACE expression in mouse neurons accelerates amyloid plaque pathology. J. Neural. Transm. 2004, 111, 413 - 425.
74. Willem, M.; Dewachter, I; Smyth, N.; Van Dooren, T.; Borghgraef, P.; Haass, C.; Van Leuven, F. site Amyloid Precursor Protein cleaving enzyme I increases amyloid deposition in brain parenchyma but reduces cerebrovascular amyloid angiopathy in aging BACExAPP[V717I] Double-Transgenic Mice. Am. J. Path. 2004,165,1621-1631.
75. Lee, E-B; Zhang, B.; Liu, K.; Greenbaum, E. A.; Doms, R. W.; Trojanowski, J. Q.; Lee, V. M. BACE overexpression alters the subcellular processing of APP and inhibits Abets deposition in vivo. J. Cell Biol. 2005, 168, 291-302.
76. Selkoe, D. J. Alzheimer's disease: genes, proteins, and therapy. PhysioL Rev. 2001, 81, 741-766.
77. Moss, M. L.; Bartsch, J. W. Therapeutic Benefits from Targeting of ADAM Family Members. Biochemistry 2004, 43, 7227-7235.
78. Buxbaum, J. D.; Liu, K. N.; Luo, Y.; Slack, J. L.; Stocking, K. L.; Peschon, J; J.; Johnson, R. S.; Castner, B. J.; Cerretti, D. P.; Black, R. A. Evidence that Tumour Necrosis Factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 1998, 273, 27765-27767.
79. Lammich, S.; Kojro, E.; Postina, R.; Gilbert, S.; Pfieffer, R.; Jasionowski, M.; Haas, C.; Fahrenholz, F. Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 3922-3927.
80. Postina, R.; Schroeder, A.; Dewachter, A.; Bohl, J.; Schmitt, U.; Kojro, E.; Prinzen, C.; Endres, K.; Hiemke, C.; Blessing, M.; Flamez, P.; Dequenne, A.; Godaux, E.; van Leuven, F. Fahrenholz, F. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest. 2004, 113, 1456-1464.
81. Lambert, M. P.; Barlow, A. K.; Chromy, B. A.; Edwards, C.; Freed, R.; Liosatos, M.; Morgan, T. E.; Rozovsky, L; Trommer, B.; Viola, K. L.; Wals, P.; Zhang, C.; Finch, C. E.; Kraff, G. A.; Klein, W. L. Diffusible, nonfibrillar ligands derived from Abetal-42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 1998, 95, 6448- 6453.
82. Kim, H. J.; Chae, S. C.; Lee, D. K.; Chromy, B.; Lee, S. C.; Park, Y. C.; Klein, W. L.; Kraff G. A.; Hong, S. T. Selective neuronal degeneration induced by soluble oligomeric amyloid beta protein. FASEB J 2003, 17, 118-120.
83. Walsh, D. M.; Klyubin, L; Fadeeva, J. V.; Cullen, W. K.; Anwyl, R.; Wolfe, M. S.; Rowan, M. J.; Selkoe, D. J. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002, 416, 535-539.
84. Wang, Q.; Walsh, D. M.; Rowan, M. J.; Selkoe, D. J.; Anwyl, R. Block of Long-Term Potentiation by naturally secreted and synthetic amyloid β-peptide in Hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as Metabotropic Glutamate receptor type 5. J. Neurosci. 2004, 24, 3370-3378.
85. Ashe, K. H. Mechanisms of memory loss in A and tau mouse models. Mol. Mech. Neurodeg. 2005, 33, 591-594.
86. Sisodia, S. S.; Koo, E. H.; Hoffman, P. N.; Perry, G.; Price, D. L. Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. J. Neurosci. 1993, 13, 3136-3142.
87. Kamal, A.; Almenar-Queralt, A.; LeBlanc, J. F.; Roberts, E. A.; Goldstein, L. S. Kinesin- mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 2001, 414, 643-648.
88. Lazarov, O.; Morfini, G. A.; Lee, E. B.; Farah, M. H.; Szodorai, A.; DeBoer, S. R.; Koliatsos, V. E.; Kins, S.; Lee, V. M.; Wong, P. C.; Price, D. L.; Brady, S. T.; Sisodia, S. S. Axonal transport, amyloid, precursor protein, kinesin-1, and the processing apparatus: revisited. J. Neurosci. 2005, 25, 2386-2395.
89. Stokin, G. B.; Lillo, C.; Falzone, T. L.; Brusch, R. G.; Rockenstein, E.; Mount, S. L.; Raman, R.; Davies, P.; Masliah, E.; Williams, D. S.; Goldstein, L. S. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science 2005, 307, 1282-1288.
90. Takahashi, R. H.; Almeida, C. G.; Kearney, P. F.; Yu, F.; Lin, M. T.; Milner, T. A.; Gouras, G. K. Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain. J. Neurosci. 2004, 24, 3592-3599.
91. Oddo, S.; Caccamo, A.; Shepherd, J. D.; Murphy, M. P.; Golde, T. E.; Kayed, R.; Metherate, R.; Mattson, M. P.; Akbari, Y.; LaFerla, F. M. Triple-transgeric model of Alzheimer's disease with plaques and tangles. Intracellular abeta and synaptic dysfunction. Neuron 2003, 39, 409-421.
92. 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. U.S.A. 1988, 85, 4051-4055.
93. Alonso, A. D. C.; Grundke-Iqbal, L; lqbal, K. Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nature Med. 1996, 2, 783-787.
94. Goedert, M.; Spillantini, M. G.; Potier, M. C.; Ulrich, J.; Crowther, R. A. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J 1989, 8, 393-399.
95. Rademakers, R.; Cruts, M.; van Broeckhoven, C. The role of tau (MAPT) in fromotemporal dementia and related tauopathies. Hum. Mutat. 2004, 24, 277-295.
96. Hutton, M.; Lendon, C. L.; Rizzu, P.; Baker, M.; Froelich, S.; Houlden, H.; Pickering- Brown, S.; Chakraverty, S.; Isaacs, A.; Grover, A.; Hackett, J.; Adamson, J.; Lincoln, S.; Dickson, D.; Davies, P.; Petersen, R. C.; Stevens, M.; de Graaff, E.; Watiters, E.; van Baren, J.; Hillebrand, M.; Joosse, M.; Kwon, J. M.; Nowotny, P.; Che, L. K.; Norton, J.; Morris, J. C.; Reed, L. A.; Trojanowski, J.; Basun, H.; Lannfelt, L.; Neystat, M.; Fahn, S.; Dark, F.; Tannenberg, T.; Dodd, P. R.; Hayward, N.; Kwok, J. B.; Schofield, P. R.; Andreadis, A.; Snowden, J.; Craufurd, D.; Neary, D.; Owen, F.; Oostra, B. A.; Hardy, J.; Goate, A.; van Swieten, J.; Mann, D.; Lynch, T.; Heutink, P. Association of missense and 50-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998, 393, 702-705.
97. Hutton, M. Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurology 2001, 56, S21-S25.
98. Hasegawa, M.; Smith, M. J.; Goedert, M. Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett. 1998, 437, 207-210.
99. Braak, H.; Braak, E. Neuropathological staging of Alzheimer- related changes. Acta Neuropathol. (Berl.) 1991, 82, 239-259.
100. Braak, H., Braak, E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol. Aging 1995, 16, 271-278.
101. Delacourte, A.; Sergeant, N.; Champain, D.; Wattez, A.; Maurage, C.-A.; Lebert, F.; Pasquier, F.; David, J.-P. Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer's disease. Neurology 2002, 59, 398-407.
102. Zheng, H.; Jiang, M.; Trumbauer, M. E.; Sirinathsinghji, D. J.; Hopkins, R.; Smith, D. W.; Heavens, R. P.; Dawson, G. R.; Boyce, S.; Conner, M. W.; Stevens, K. A.; Slunt, H. H.; Sisoda, S. S.; Chen, H Y.; Van der Ploeg, L. H. beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 1995, 81, 525-531.
103. Donoviel, D. B.; Hadjamonakis, A.; Ikeda, M.; Zheng, H.; St George Hyslop, P.; Bernstein, A. Mice lacking both presenilin I genes exhibit early embryonic patterning defects. Genes Dev. 1999, 13, 2801-2810.
104. Yu, H.; Santa, C. A.; Choi, S. Y.; Sun, L. D.; Yang, X.; Handler, M.; Kawarabayashi, T.; Younkin, L.; Fedeles, B.; Wilson, M. A.; Younkin, S.; Kandel, E. R.; Kirkwood, A.; Shen, J. APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron 2001, 31, 713-726.
105. rd.; Kandel, E. R.; Duff, K.; Kirkwood, A.; Shen, J. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 2004, 42, 23-36.
106. Saito, T.; Iwata, N.; Tsubuki, S.; Takaki, Y.; Takano, J.; Huang, S. M.; Suemoto, T.; Higuchi, M.; Saido, T. C. Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat. Med. 2005, 11, 434-439.
107. Kobayashi, D. T.; Chen, K. S. Behavioral phenotypes of amyloid- based genetically modified mouse models of Alzheirnees disease. Genes Brain Behav. 2005, 4, 173-196.
108. Price, D. L.; Sisodia, S. S. Cellular and molecular biology of Alzheimer's disease and animal models. Annu. Rev. Med. 1994, 45, 435-446.
109. Hyman, B. T. Down syndrome and Alzheimer disease. Prog. Clin. Biol. Res. 1992, 379, 123-142.
110. Cairns, N. J. Molecular neuropathology of transgenic mouse models of Down syndrome. J. Neural Transm. Suppl. 2001, 61, 289-301.
111. O'Dolierty, A.; Ruf, S.; Mulligan, C.; Hildreth, V.; Errington, M. L.; Cooke, S.; Sesay, A.; Modino, S.; Vanes, L.; Hernandez, D.; Linehan, J. M.; Sharpe, P. T.; Brandner, S.; Bliss, T. V.; Henderson, D. J.; Nizetic, D.; Tybulewicz, V. L.; Fisher, E. M. An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science 2005, 309, 2033-2037.
112. Lamb, B. T.; GearhaM J. D. YAC transgenics and the study of genetics and human disease. Curr. Opin. Genet. Dev. 1995, 5, 342-348.
113. Quon, D.; Wang, Y.; Catalano, R.; Scardina, J. M.; Murkami, K.; Cordell, B. Formation of b-amyloid protein deposits in brains of transgenic mice. Nature 1991, 352, 239-241.
114. Chen, K. S.; Masliah, E.; Grajeda, H.; Guido, T.; Huang, J.; Khan, K.; Motter, R.; Soriano, F.; Games, D. Neurodegenerative Alzheimer-like pathology in PDAPP 717V-->F transgenic mice. Prog. Brain Res. 1998, 117, 327-334
115. Kawarabayashi, T.; Younkin, L. H.; Saido, T. C.; Shoji, M.; Ashe, K. H.; Younkin, S. G. Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimees disease. J. Neurosci. 2001, 21, 372-381.
116. Westerman, M. A.; Cooper-Blacketer, D.; Mariash, A.; Kotilinek, L.; Kawarabayashi, T.; Younkin, L. H.; Carlson, G. A.; Younkin, S. G.; Ashe, K. H. The relationship between Abeta and memory in the Tg2576 mouse model of Alzheirnees disease. J. Neurosci. 2002, 22, 1858-1867.
117. Van Dam, D.; Vloeberghs, E.; Abramowsld, D.; Staufenbiel, M.; De Deyn, P. P. APP23 mice as a model of Alzheimer's disease: an example of a transgenic approach to modeling a CNS disorder. CNS SPectr. 2005, 10, 207-222.
118. Dewachter, L; van Dorpe, J.; Spittaels, K.; Tesseur, I.; Van Den Haute, C.; Moechars, D.; Van Leuven, F. Modeling Alzheimer's disease in transgenic mice: effect of age and of presenilin1 on amyloid biochemistry and pathology in APP/London mice. Exp. Gerontol. 2000, 35, 831-841.
119. Mucke, L.; Masliah, E.; Yu, G.Q.; Mallory, M.; Rockenstein, E. M.; Tatsuno, G.; Hu, K.; Kholodenko, D.; Johnson-Wood, K; McConlogue, L. Higb-level neuronal expression of Abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 2000, 20, 4050-4058.
120. Chishti, M. A.; Yang, D. S.; Janus, C.; Phinney, A. L.; Horne, P.; Pearson, J.; Strome, R.; Zuker, N.; Loukides, J.; French, J.; Turner, S.; Lozza, G.; Grilli, M.; Kunicki, S.; Morissette, C.; Paquette, J.; Gervais, F.; Bergeron, C.; Fraser, P. E.; Carlson, G. A.; George-Hyslop, P. S.; Westaway, D. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J. Biol Chem. 2001, 276, 21562-21570.
121. Rockenstein, E.; Mallory, M.; Mante, M.; Sisk A.; Masliah, E. Early formation of mature amyloid-beta protein deposits in a mutant APP transgenic model depends on levels of Abeta(1-42). J. Neurosci. Res. 2001, 66, 573-582.
122. Duff, K.; Eckman, C.; Zehr, C.; Yu, X.; Prada, C.H.; Perez-Tur, J.; Hutton, M.; Buee, L.; Harigaya, Y.; Yager, D.; Morgan, D.; Gordon, M. N.; Holcomb, L.; Refolo, L.; Zenk, B.; Hardy, J.; Younkin, S. Increased amyloid β 42 (43) in brains of mice expressing mutant presenilin-1. Nature 1996, 383, 710-713.
123. Borchelt, D. R.; Thinakaran, G.; Eckman, C. B.; Lee, M. K.; Davenport, F.; Ratovitsky, T.; Prada, C. M.; Kim, G.; Seekins, S.; Yager, D.; Slunt, H. H.; Wang, R.; Seeger, M.; Levey, A. I.; Gandy, S. E.; Copeland, N. G.; Jenkins, N. A.; Price, D. L.; Younkin, S. G.; Sisodia, S. S. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abetal-42/1-40 ratio in vitro and in vivo. Neuron 1996, 17, 1005-13.
124. Borchelt, D. R.; Ratovitski, T.; van Lare, J.; Lee, M.K.; Gonzales, V.; Jenkins, N. A.; Copeland, N. G.; Price, D. L.; Sisodia, S. S. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 1997, 19, 939-945.
125. Holcomb, L.; Gordon, M. N.; McGowan, E.; Yu, X.; Benkovic, S.; Jantzen, P.; Wright, K.; Saad, I.; Mueller, R.; Morgan, D.; Sanders, S.; Zehr, C.; O'Campo, K.; Hardy, J.; Prada, C. M.; Eckman, C.; Younkin, S.; Hsiao, K.; Duff, K. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat. Med. 1998, 4, 97-100.
126. Citron, M.; Westaway, D.; Xia, W.; Carlson, G.; Diehl, T.; Levesque, G.; Johnson-Wood, K.; Lee, M.; Seubert, P.; Davis, A.; Kholodenko, D.; Motter, R.; Sherrington, R.; Perry, B.; Yao, H.; Strome, R.; Lieberburg, I.; Rommens, J.; Kim, S.; Schenk, D.; Fraser, P.; St George Hyslop, P.; Selkoe, D. J. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat. Med, 1997, 3, 67-72.
127. Phinney, A. L.; Horne, P.; Yang, J.; Janus, C.; Bergeron, C.; Westaway, D. Mouse models of Alzheimer's disease: the long and filamentous road. Neurol. Res. 2003, 25, 590-600.
128. Ishihara, T.; Hong, M.; Zhang, B.; Nakagawa, Y.; Lee, M. K.; Trojanowski, J. Q.; Lee, V. M. Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 1999, 24, 751-762.
129. Probst, A.; Gotz, J.; Wiederhold, K. H.; Tolnay, M.; Mistl, C.; Jaton, A. L,; Hong, M.; Ishihara, T.; Lee, V. M.; Trojanowski, J. Q.; Jakes, R.; Crowther, R. A.; Spillantini, M. G.; Burki, K.; Goedert M. Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol. (Berl). 2000, 99, 469-481.
130. Lewis, J.; McGowan, E.; Rockwood, J.; Melrose, H.; Nacharaju, P.; Van Slegtenhorst, M.; Gwinn-Hardy, K.; Paul Murphy. M.; Baker, M.; Yu, X.; Duff, K.; Hardy, J.; Corral, A.; Lin, W. L.; Yen, S. H.; Dickson, D. W.; Davies, P.; Hutton, M. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 2000, 25, 402-405.
131. Gotz, J.; Chen, F.; van Dorpe, J.; Nitsch, R. M. Formation of Neurofibrillary tangles in P3011 tau transgenic mice induced by Abeta 42 fibrils. Science 2000, 293, 1491-1495.
132. Lim, F.; Hernandez, F.; Lucas, J. J.; Gomez-Ramos, P.; Moran, M. A.; Avila, J. FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain. Mol. Cell Neurosci. 2001, 18, 702-714:
133. Tatebayashi, Y.; Miyasaka, T.; Chui, D. H.; Akagi, T.; Mishima, K.; Iwasaki, K.; Fujiwara, M.; Tanemura, K.; Murayama, M.; Ishiguro, Y.; Planel. E.; Sato, S.; Hashikawa, T.; Takashima, A. Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc. Natl. Acad Sci. U. S. A. 2002, 99, 13896-13901.
134. Chae, T.; Kwon, Y. T.; Bronson, R.; Dikkes, P.; Li, E.; Tsai, L. H. Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 1997, 18, 29-42.
135. Ohshima, T.; Ward, J. M.; Huh, C. G.; Longenecker, G.; Veeranna; Pant, H. C.; Brady, R. O.; Martin, L. J.; Kulkarni, A. B. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl. Acad. Sci. U S. A. 1996, 93, 11173-11178.
136. Ko, J.; Humbert, S.; Bronson, R. T.; Takahashi, S.; Kulkami, A. B.; Li, E.; Tsai, L. H. p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment. J. Neurosci. 2001, 21, 6758-6771.
137. Smith, D. S.; Tsai, L. H. Cdk5 behind the wheel: a role in trafficking and transport? Trends Cell Biol. 2002, 12, 28-36.
138. Flaherty, D. B.; Soria, J. P.; Tomasiewicz, H. G.; Wood, J. G. Phosphorylation of human tau protein by microtubule-associated knases: GSK3beta and cdk5 are key participants. J. Neurosci. Res. 2000, 62, 463-472.
139. Lee, M. S.; Kwon, Y. T.; Li, M.; Peng, J.; Friedlander, R. M.; Tsai, L. H. Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 2000, 405, 360-364.
140. Patrick, G. N.; Zukerberg, L.; Nikolic, M.; de la Monte, S.; Dikkes, P.; Tsai, L. H. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 1999, 402, 615-622.
141. Baumann, K.; Mandelkow, E. M.; Biernat, J.; Piwnica-Worms, H.; Mandelkow, E. Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett. 1993, 336, 417-424.
142. Ahlijanian, M. K.; Barrezueta, N. X.; Williams, R. D.; Jakowski, A.; Kowsz, K. P.; McCarthy, S.; Coskran, T.; Carlo, A.; Seymour, P. A.; Burkhardt, J. E.; Nelson, R. B.; McNeish, J. D. Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an, activator of cdk5. Proc. Natl. Acad. Sci. USA 2000, 97, 2910-2915.
143. Noble, W.; Olm, V.; Takata, K.; Casey, E.; Mary, O.; Meyerson, J.; Gaynor, K.; LaFrancois, J.; Wang, L.; Kondo, T.; Davies. P.; Burns, M.; Veeranna; Nixon, R.; Dickson, D.; Matsuoka, Y.; Ahlijanian, M.; Lau, L. F.; Duff, K. Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 2003, 38, 555-565.
144. Ruberti, F.; Capsoni, S.; Comparini, A.; Di Daniel, E.; Franzot, J.; Gonfloni, S.; Rossi, G.; Berardi, N.; Cattaneo, A. Phenotypic knockout of nerve growth factor in adult transgenic mice reveals severe deficits in basal forebrain cholinergic neurons, cell death in the spleen, and skeletal muscle dystrophy. J. Neurosci. 2000, 20, 2589-2601.
145. Crowley, C.; Spencer, S. D.; Nishimura, M. C.; Chen, K. S.; Pitts-Meek, S.; Armanini, M. P.; Lanway, H. L.; McMahon, S. B.; Shelton, D. L.; Levinson, A. D.; Phillips, H. S. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 1994, 76, 1001-1011.
146. Capsoni, S.; Ugolini, G.; Comparini, A.; Ruberti, F.; Berardi, N.; Cattaneo, A. Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 6826-6831.
147. Capsoni, S.; Giannotta, S.; Cattaneo, A. Beta-amyloid plaques in a model for sporadic Alzheimer's disease based on transgenic anti-nerve growth factor antibodies. Mol. Cell Neurosci. 2002, 21, 15-28.
148. De Rosa, R.; Garcia, A. A.; Braschi, C.; Capsoni, S.; Maffei, L.; Berardi, N.; Cattaneo, A. Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proc. Natl. Acad. Sci. U S. A. 2005, 102, 3811-3816.
149. Connor, B.; Young, D.; Yan, Q.; Faull, R. L.; Synek, B.; Dragunow, M. Brain-derived neurotrophic factor is reduced in Alzheimer's disease. Brain Res. Mol. Brain Res. 1997, 49, 71-81.
150. Connor, B.; Dragunow, M. The role of neuronal growth factors in neurodegenerative disorders of the human brain. Brain Res. Brain Res. Rev. 1998, 27, 1-39.
151. Tuszynski, M. H.; Thal, L.; Pay, M.; Salmon, D. P.; U, H. S.; Bakay, R.; Patel, P.; Blesch, A.; Vahlsing, H. L.; Ho, G.; Tong, G.; Poddn, S. G.; Fallon, J.; Hansen, L.;, Mufson, E. J.; Kordower, J. H.; Gall, C.; Conner, J. A phase 1 clinical trial of nerve growth actor gene therapy for Alzheimer disease. Nat. Med. 2005, 11, 551-555.
152. Bales, K. R.; Dodart, J. C.; DeMattos, R. B.; Holtzman, D. M.; Paul, S. M. Apolipoprotein E, amyloid, and Alzheimer disease. Mol. Interv. 2002, 2, 363-375.
153. Tanzi, R. E.; Moir, R. D.; Wagner, S. L. Clearance of Alzheimer's Abeta peptide: the many roads to perdition. Neuron 2004, 43, 605-608.
154. Oddo, S.; Caccamo, A.; Kitazawa, M,; Tseng, B. P.; LaFerla, F. M. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol. Aging 2003, 24, 1063-1070.
155. Oddo, S.; Billings, L.; Kesslak, J. P.; Cribbs, D. H.; LaFerla, F. M. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 2004, 43, 321-332
156. Kayed, R.; Head, E.; Thompson, J. L.; McIntire, T. M.; Milton, S. C.; Cotman, C. W.; Glabe, C. G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003, 300, 486-489.
157. Oddo, S.; Caccamo, A.; Tran, L.; Lambert, M. P.; Glabe, C. G.; Klein, W. L.; Laferla, F. M. Temporal profile of Abeta oligomerization in an in vivo model of Alzheimer's disease: A link between Abeta and tau pathology. J. Biol. Chem. 2005 Nov 10 [Epub ahead of print].
158. Billings, L. M.; Oddo, S.; Green, K. N.; McGaugh, J. L.; LaFerla, F. M. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 2005, 45, 675-688
159. Golde, T. E.; Janus, C. Homing in on intracellular Abeta? Neuron 2005, 45, 639-642
160. Calhoun, M. E.; Wiederhold, K. H.; Abramowski, D.; Phinney, A. L.; Probst, A.; Sturchler-Pierrat, C.; Staufenbiel, M.; Sommer, B.; Jucker, M. Neuron loss in APP transgenic mice. Nature 1998, 395, 755-756.
161. Schmitz, C.; Rutten, B. P.; Pielen, A.; Schafer, S.; Wirths, O.; Tremp, G.; Czech, C.; Blanchard, V.; Multhaup, G.; Rezaie, P.; Korr, H.; Steinbusch, H. W.; Pradier, L.; Bayer, T. A. Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease. Am. J. Pathol. 2004, 164, 1495-1502.
162. Blanchard, V.; Moussaoui, S.; Czech, C.; Touchet, N.; Bonici, B.; Planche, M.; Canton, T.; Jedidi, I.; Gohin, M.; Wirths, O.; Bayer, T. A.; Langui, D.; Duyckaerts, C.; Tremp, G.; Pradier, L. Time sequence of maturation of dystrophic neurites associated with Aβ deposits in APP/ PS1 transgenic mice. Exp. Neurol. 2003, 184, 247-263.
163. Casas, C.; Sergeant, N.; Itier, J. M.; Blanchard, V.; Wirths, O.; van der Kolk, N.; Vingtdeux, V.; van de Steeg, E.; Ret, G.; Canton, T.; Drobecq, H.; Clark, A.; Bonici, B.; Delacourte, A.; Benavides, J.; Schmitz, C.; Tremp, G.; Bayer, T. A.; Benoit, P.; Pradier, L. Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am. J. Pathol. 2004, 165, 1289-1300.
164. Sergeant, N.; Bombois, S.; Ghestem, A.; Drobecq, H.; Kostanjevecki, V.; Missiaen, C.; Wattez, A.; David, J. P.; Vanmechelen, E.; Sergheraert, C.; Delacourte, A. Truncated beta-amyloid peptide species in pre-clinical Alzheimer's disease as new targets for the vaccination approach. J. Neurochem. 2003, 85, 1581-1591.
165. Saido, T. C.; Iwatsubo, T.; Mann, D. M.; Shimada, H.; Ihara, Y.; Kawashima, S. Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron 1995, 14, 457-466.
166. Russo, C.; Schettini, G.; Saido, T. C.; Hulette, C.; Lippa, C.; Lannfelt, L.; Ghetti, B.; Gambetti, P.; Tabaton, M.; Teller, J. K. Presenilin-1 mutations in Alzheimer's disease. Nature 2000, 405, 531-532.
167. Tekirian, T. L.; Saido, T. C.; Markesbery, W. R.; Russell, M. J.; Wekstein, D. R.; Patel, E.; Geddes, J. W. N-terminal heterogeneity of parenchymal and cerebrovascular Abets deposits. J. Neuropathol. Exp. Neurol. 1998, 57, 76-94.
168. Harigaya, Y.; Saido, T. C.; Eckman, C. B.; Prada, C. M.; Shoji, M.; Younkin, S. G. Amyloid beta protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer's disease brain. Biochem. Biophys. Res. Commun. 2000, 276, 422-427.
169. McGowan, E.; Pickford, F.; Kim, J.; Onstead, L.; Eriksen, J.; Yu, C.; Skipper, L.; Murphy, M. P.; Beard, J.; Das, P.; Jansen, K.; Delucia, M.; Lin, W.L.; Dolios, G.; Wang, R.; Eckman, C. B.; Dickson, D. W.; Hutton, M.; Hardy, J.; Golde, T. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 2005, 47, 191-199.
170. Mattson, M. P. Pathways towards and away from Alzheimer's disease. Nature 2004, 430, 631-639.
171. Yankner, B. A.; Dawes, L. R.; Fisher, S.; Villa-Komaroff, L.; Oster-Granite, M. L.; Neve, R. L. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 1989, 245, 417-420.
172. Vidal, R.; Frangione, B.; Rostagno, A.; Mead, S.; Revesz, T.; Plant, G.; Ghiso, J. A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 1999, 399, 776-781.
173. Vidal, R.; Revesz, T.; Rostagno, A.; Kim, E.; Holton, J. L.; Bek, T.; Bojsen-Moller, M.; Braendgaard, H.; Plant, G.; Ghiso, J.; Frangione, B. A decamer duplication in the 3# region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 4920-4925.
174. Herzig, M. C.; Winkler, D. T.; Burgermeister, P.; Pfeifer, M.; Kohler, E.; Schmidt, S. D.; Danner, S.; Abramowski, D.; Sturchler-Pierrat, C.; Burki, K.; van Duinen, S.G.; Maat- Schieman, M. L.; Staufenbiel, M.; Mathews, P. M.; Jucker, M. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat. Neurosci. 2004, 7, 954-960.
175. Maat-Schieman, M. L.; van Duinen, S. G.; Bomebroek, M.; Haan, J.; Roos, R. A, Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). II. A review of histopathological aspects. Brain Pathol. 1996, 6, 115-120.
176. Castano, E. M.; Prelli, F.; Soto, C.; Beavis, R.; Matsubara, E.; Shoji, M.; Frangione B. The length of amyloid-beta in hereditary cerebral hemorrhage with amyloidosis, Dutch type. Implications for the role of amyloid-beta 142 in Alzheimer's disease. J. Biol Chem. 1996, 271, 32185-32191.
177. Wisniewski, T.; Ghiso, J.; Frangione, B. Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochem. Biophys. Res. Commun. 1991, 179, 1247-1254.
178. Braak, H.; Braak, E. Evolution of neuronal changes in the course of Alzheimer's disease. J. Neural Transm. Suppl. 1998, 53, 127-140.
179. Walsh, D. M.; Selkoe, D. J. Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron 2004, 44, 181-193.
180. Klein, W. L.; Stine, W. B.Jr.; Teplow, D. B. Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer's disease. Neurobiol. Aging 2004, 25, 569-580.
181. Walsh, D. M.; Klyubin, I.; Shankar, G. M.; Townsend, M.; Fadeeva, J. V.; Betts, V.; Podlisny, M. B.; Cleary, J. P.; Ashe, K. H.; Rowan, M. J.; Selkoe, D. J. The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic intervention. Biochem. Soc. Trans. 2005, 33, 1087-1090.
182. Kirkitadze, M. D.; Condron, M. M.; Teplow, D. B. Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. J. Mol. Biol. 2001, 312, 1103 -1119.
183. Stine, W. B.Jr.; Dahlgren, K. N.; Krafft, G. A.; LaDu, M. J. In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis. J. Biol. Chem. 2003, 278, 11612-11622.
184. Stine, W. B.Jr.; Snyder, S. W.; Ladror, U. S.; Wade, W. S.; Miller, M. F.; Perun, T. J.; Holzman, T. F.; Krafft G. A. The nanometer-scale structure of amyloid-beta visualized by atomic force microscopy. J. Protein Chem. 1996, 15, 193-203.
185. Wang, H. W.; Pasternak, J. F.; Kuo, H.; Ristic, H.; Lambert, M. P.; Chromy, B.; Viola, K. L.; Klein, W. L.; Stine, W. B.; Krafft, G. A.; Trommer, B. L. Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res. 2002, 924, 133-140.
186. Kim, J. H.; Anwyl, R.; Sub, Y. H.; Djamgoz, M. B.; Rowan, M. J. Use-dependent effects of amyloidogenic fragments of β-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo. J. Neurosci. 2001, 21, 1327-1333.
187. Podlisny, M. B.; Ostaszewski, B. L.; Squazzo, S. L.; Koo, E. H.; Rydell, R. E.; Teplow, D. B.; Selkoe, D. J. Aggregation of secreted amyloid beta-protein into sodium dodecyl sulfate-stable oligomers in cell culture. J. Biol. Chem. 1995, 270, 9564-9570.
188. Walsh, D. M.; Tseng, B. P.; Rydel, R. E.; Podlisny, M. B.; Selkoe, D. J. The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry 2000, 39, 10831-10839.
189. Walsh, D. M.; Klyubin, I.; Fadeeva, J. V.; Cullen, W. K.; Anwyl, R.; Wolfe, M. S.; Rowan, M. J.; Selkoe, D. J. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002, 416, 535-539.
190. Klyubin, I.; Walsh, D. M.; Lemere, C. A.; Cullen, W. K.; Shankar, G. M.; Betts, V.; Spooner, E. T.; Jiang, L.; Anwyl, R.; Selkoe, D. J.; Rowan, M. J. Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nat. Med. 2005, 11, 556-561.
191. Takahashi, R. H.; Milner, T. A.; Li, F.; Nam, E. E.; Edgar, M. A.; Yamaguchi, H.; Beal, M. F.; Xu, H.; Greengard, P.; Gouras, G. K. Intraneuronal Alzheimer Aß42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am. J. Pathol. 2002, 161, 1869-1879.
192. Kawarabayashi, T.; Shoji, M.; Younkin, L. H.; Wen-Lang, L.; Dickson, D. W.; Murakami, T.; Matsubara, E.; Abe, K.; Ashe, K. H.; Younkin, S. G. Dimeric amyloid beta protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer's disease. J. Neurosci. 2004, 24, 3801-3809.
193. Cleary, J. P.; Walsh, D. M.; Hofmeister, J. J.; Shankar, G. M.; Kuskowski, M. A.; Selkoe, D. J.; Ashe, K. H. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat. Neurosci. 2005, 8, 79-84.
194. O'Hare, E.; Levine, A. S.; Semotuk, M. T.; Tierney, K. J.; Shephard, R. A.; Grace, M. K.; Cleary, J. Utilization of a novel model of food reinforced behavior involving neuropeptide Y, insulin, 2-deoxy-d-glucose and naloxone. Behav. Pharmacol. 1996, 7, 742-753
195. Klein, W. L.; Krafft, G. A.; Finch, C. E. Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 2001, 24, 219-224.
196. Lee, V. M.; Kenyon, T. K.; Trojanowski, J. Q. Transgenic animal models of tauopathies. Biochim. Biophys. Acta. 2005, 1739, 251-259.
197. Ramsden, M.; Kotilinek, L.; Forster, C.; Paulson, J.; McGowan, E.; Santacruz, K.; Guimaraes, A.; Yue, M.; Lewis, J.; Carlson, G.; Hutton, M.; Ashe, K. H. Age-Dependent Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment in a Mouse Model of Human Tauopathy (P301L). J. Neurosci. 2005, 25, 10637-10647.
198. Saudou, F.; Finkbeiner, S.; Devys, D.; Greenberg, M. E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998, 95, 55-66.
199. Arrasate, M.; Mitra, S.; Schweitzer, E. S.; Segal, M. R.; Finkbeiner, S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 2004, 431, 805-810.
200. Dovey, H. F.; John, V.; Anderson, J. P.; Chen, L. Z.; de Saint Andrieu, P.; Fang, L. Y.; Freedman, S. B.; Folmer, B.; Goldbach, E.; Holsztynska, E. J.; Hu, K. L.; Johnson-Wood, K. L.; Kennedy, S. L.; Kholodenko, D.; Knops, J. E.; Latimer, L. H.; Lee, M.; Liao, Z.; Lieberburg, I. M.; Motter, R. N.; Mutter, L. C.; Nietz, J.; Quinn, K. P.; Sacchi, K. L.; Seubert, P. A.; Shopp, G. M.; Thorsett, E. D.; Tung, J. S.; Wu, J.; Yang, S.; Yin, C. T.; Schenk, D. B.; May, P. C.; Altstiel, L. D.; Bender, M. H.; Boggs, L. N.; Britton, T. C.; Clemens, J. C.; Czilli, D. L.; Dieckman-McGinty, D. K.; Droste, J. J.; Fuson, K. S.; Gitter, B. D.; Hyslop, P. A.; Johnstone, E. M.; Li, W. Y.; Little, S. P.; Mabry, T. E.; Miller, F. D.; Audia, J. E. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J. Neurochem. 2001, 76, 173-181.
201. Lanz, T. A.; Himes, C. S.; Pallante, G.; Adams, L.; Yamazaki, S.; Amore, B.; Merchant, K. M. The gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S- phenylglycine t-butyl ester reduces A beta levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J. Pharmacol. Exp. Ther. 2003, 305, 864-871.
202. Lanz, T. A.; Hosley, J. D.; Adams, W. J.; Merchant, K. M. Studies of Abeta pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2- hydroxyethanoyl]-Nl-[(7S)-5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo[b,d] azepin-7-yl]-L- alaninamide (LY-411575). J. Pharmacol. Exp. Ther. 2004, 309, 49-55.
203. Comery, T. A.; Martone, R. L.; Aschmies, S.; Atchison, K. P.; Diamantidis, G.; Gong, X.; Zhou, H.; Kreft, A. F.; Pangalos, M. N.; Sonnenberg-Reines, J.; Jacobsen, J. S.; Marquis, K. L. Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease. J. Neurosci. 2005, 25, 8898-8902.
204. Best, J. D.; Jay, M. T.; Out, F.; Ma, J.; Nadin, A.; Ellis, S.; Lewis, H. D.; Pattison, C.; Reilly, M.; Harrison, T.; Shearman, M. S.; Williamson, T. L.; Atack, J. R. Quantitative measurement of changes in amyloid-beta(40) in the rat brain and cerebrospinal fluid following treatment with the gamma-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5- difluorophenyl)-2-hydroxyethnoy1]-Nl-[(7S)-5-methyl-6-oxo-6, 7-dihydro-5H- dibenzo[b,d]azepin-7-yl]-L-alaninamide] J. Pharmacol. Exp. Ther. 2005, 313, 902-908.
205. Barten, D. M.; Guss, V. L.; Corsa, J. A.; Loo, A.; Hansel, S. B.; Zheng, M.; Munoz, B.; Srinivasan, K.; Wang, B.; Robertson, B. J.; Polson, C. T.; Wang, J.; Roberts, S. B.; Hendrick, J. P.; Anderson, J. J.; Loy, J. K.; Denton, R.; Verdoorn, T. A.; Smith, D. W.; Felsenstein, K. M. Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}- secretase inhibitor. J. Pharmacol. Exp. Ther. 2005, 312, 635-643.
206. Churcher, I.; Beher, D. Gamma-secretase as a therapeutic target for the treatment of Alzheimer's disease. Curr. Pharm. Des. 2005, 11, 3363-3382.
207. Chang, W. P.; Koelsch, G.; Wong, S.; Downs, D.; Da, H.; Weerasena, V.; Gordon, B.; Devasamudram, T.; Bilcer, G.; Ghosh, A. K.; Tang, J. In vivo inhibition of Abeta production by memapsin 2 (beta-secretase) inhibitors. J. Neurochem. 2004, 89, 1409-1416.
208. Asai, M.; Hattori, C.; Iwata, N.; Saido, T. C:; Sasagawa, N.; Szabo, B.; Hashimoto, Y.; Maruyama, K.; Tanuma, S.; Kiso, Y.; Ishiura, S. The novel beta-secretase inhibitor KMI- 429 reduces amyloid beta peptide production in amyloid precursor protein transgenic and wild-type mice. J. Neurochem. 2006, 96, 533-540.
209. Schenk, D.; Hagen, M.; Seubert, P. Current progress in beta-amyloid immunotherapy. Curr. Opin. Immunol. 2004, 16, 599-606.
210. Lombardo, J. A.; Stern, E. A.;, McLellan, M. E.; Kajdasz, S. T.; Hickey, G. A.; Bacskai, B. J.; Hyman, B. T. Amyloid-beta antibody treatment leads to rapid normalization of plaque-induced neuritic alterations. J. Neurosci. 2003, 23, 10879-10883.
211. Das, P.; Howard, V.; Loosbrock, N.; Dickson, D.; Murphy, M. P.; Golde, T. E. Amyloid- beta immunization effectively reduces amyloid deposition in FcRgamma-/- knock-out mice. J. Neurosci. 2003, 23, 8532-8538.
212. Lemere, C. A.; Spooner, E. T.; LaFrancois, J.; Malester, B.; Mori, C.; Leverone, J. F.; Matsuoka, Y.; Taylor, J. W.; DeMattos, R. B.; Holtzman, D. M.; Clements, J. D.; Selkoe, D. J.; Duff, K.E. Evidence for peripheral clearance of cerebral Abeta protein following chronic, active Abeta immunization in PSAPP mice. Neurobiol. Dis. 2003, 14, 10-18.
213. Wilcock, D. M.; Munireddy, S. K.; Rosenthal, A.; Ugen, K. E.; Gordon, M. N.; Morgan, D. Microglial activation facilitates Abeta plaque removal following intracranial anti- Abeta antibody administration. Neurobiol. Dis. 2004, 15, 11-20.
214. Jensen, M. T.; Mottin, M. D.; Cracchiolo, J. R.; Leighty, R. E.; Arendash, G. W. Lifelong immunization with human beta-amyloid (1-42) protects Alzheimer's transgenic mice against cognitive impairment throughout aging. Neuroscience 2005, 130, 667-684.
215. Buttini, M.; Masliah, E.; Barbour, R.; Grajeda, H.; Motter, R.; Johnson-Wood, K.; Khan, K.; Seubert, P.; Freedman, S.; Schenk, D.; Games, D. Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer's disease. J. Neurosci. 2005, 25, 9096-9101.
216. Lee, E. B.; Leng, L. Z.; Zhang, B.; Kwong, L.; Trojanowski, J. Q.; Abel, T.; Lee, V. M. Targeting Abeta oligomers by passive immunization with a conformation selective monoclonal antibody improves learning and memory in APP transgenic mice. J. Biol. Chem. 2005, Dec 16; [Epub ahead of print].
217. Cao, X.; Sudhof, T. C. A transcriptionally active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 2001, 293, 115-20.
218. Moran, P. M.; Higgins, L. S.; Cordell, B.; Moser, P. C. Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein. Proc. Nat. Acad. Sci. USA 1995, 92, 5341-5345.
219. Koistinaho, M.; Ort, M.; Cimadevilla, J. M.; Vondrous, R.; Cordell, B.; Koistinaho, J.; Bures, J.; Higgins, L. S. Specific spatial learning deficits become severe with age in beta- amyloid precursor protein transgenic mice that harbor diffuse beta -amyloid deposits but do not form plaques. Proc. Nat. Acad. Sci. USA 2001, 98, 14675-14680.
220. Dodart, J. C.; Meziane, H.; Mathis, C.; Bales, K. R.; Paul, S. M.; Ungerer, A. Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Behav. Neurosci. 1999, 113, 982-990.
221. Chen, G.; Chen, K. S.; Knox, J.; Inglis, J.; Bernard, A.; Martin, S. J.; Justice, A.; McConlogue, L.; Games, D.; Freedman, S. B.; Morris, R. G. A learning deficit related to age and betaamyloid plaques in a mouse model of Alzheimer's disease. Nature 2000, 408, 975-979.
222. Huitron-Resendiz, S.; Sanchez-Alavez, M.; Gallegos, R.; Berg, G.; Crawford, E.; Giacchino, J. L.; Games, D.; Henriksen, S. J.; Criado, J. R. Age-independent and age- related deficits in visuospatial learning, sleep-wake states, thermoregulation and motor activity in PDAPP mice. Brain Res. 2002, 928, 126-137.
223. Chapman, P. F.; White, G. L.; Jones, M. W.; Cooper-Blacketer, D.; Marshall, V. J.; Irizarry, M.; Younkin, L.; Good, M. A.; Bliss, T. V.; Hyman, B. T.; Younkin, S. G.; Hsiao, K. K. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat. Neurosci. 1999, 2, 271-276.
224. Corcoran, K. A.; Lu, Y.; Turner, R. S.; Maren, S. Overexpression of hAPPswe impairs rewarded alternation and contextual fear conditioning in a transgenic mouse model of Alzheimer's disease. Learning and Memory 2002, 9, 243-252.
225. Kelly, P. H.; Bondolfi, L.; Hunziker, D.; Schlecht, H. P.; Carver, K.; Maguire, E.; Abramowski, D.; Wiederhold, K. H.; Sturchler-Pierrat, C.; Jucker, M.; Bergmann, R.; Staufenbiel, M.; Sommer, B. Progressive age-related impairment of cognitive behavior in APP23 transgenic mice. Neurobiol. Aging 2003, 24, 365-378.
226. Van Dam, D.; D'Hooge, R.; Staufenbiel, M.; Van Ginneken, C.; Van Meir, F.; De Deyn, P. P. Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur. J. Neurosci. 2003, 17, 388-396.
227. Moechars, D.; Lorent, K.; Van Leuven, F. Premature death in transgenic mice that overexpress a mutant amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. Neuroscience 1999, 91, 819-830.
228. Moechars, D.; Dewachter, I.; Lorent, K.; Reverse, D.; Baekelandt, V.; Naidu, A.; Tesseur, I.; Spittaels, K.; Haute, C. V.; Checler, F.; Godaux, E.; Cordell, B.; Van Leuven, F. Early phenotypic changes in transgenic: mice that overexpress different mutants of amyloid precursor protein in brain. J. Biol. Chem. 1999, 274, 6483-6492.
229. Palop, J. J.; Jones, B.; Kekonius, L.; Chin, J.; Yu, G. Q.; Raber, J.; Masliah, E.; Mucke, L. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 9572-9577.
230. Janus, C.; Pearson, J.; McLaurin, J.; Mathews, P. M.; Jiang, Y.; Schmidt, S. D.; Chishti, M. A.; Horne, P.; Heslin, D.; French, J.; Mount, H. T.; Nixon, R. A.; Mercken, M.; Bergeron, C.; Fraser, P. E.; St George-Hyslop, P.; Westaway, D. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 2000, 408, 979-982.
231. Janus, C. Search strategies used by APP transgenic mice during navigation in the Morris water maze. Learning and Memory 2004, 11, 337-346.
232. Lovasic, L.; Bauschke, H.; Janus, C. Working memory impairment in a transgenic amyloid precursor protein TgCRND8 mouse model of Alzheimer's disease. Genes Brain Behav. 2005, 4, 197-208.
233. Arendash, G. W.; King, D. L.; Gordon, M. N.; Morgan, D.; Hatcher, J. M.; Hope, C. E.; Diamond, D. M. Progressive, agerelated behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes. Brain Res. 2001, 891, 42-53.
234. Gordon, M. N.; King, D. L.; Diamond, D. M.; Jantzen, P. T.; Boyett, K. V.; Hope, C. E.; Hatcher, J. M.; DiCarlo, G.; Gottschall, W. P.; Morgan, D.; Arendash, G. W. Correlation between cognitive deficits and Abeta deposits in transgenic APP_PSI mice. Neurobiol. Aging 2001, 22, 377-385.
235. Higuchi, M.; Ishibara, T.; Zhang, B.; Hong, M.; Andreadis, A.; Trojanowski, J.; Lee, V. M. Transgenic mouse model of taupathies with glial pathology and nervous system degeneration. Neuron 2002, 35, 433-446.
236. Lewis, J.; Dickson, D. W.; Lin, W. L.; Chisholm, L.; Corral, A.; Jones, G.; Yen, S. H.; Sahara, N.; Skipper, L.; Yager, D.; Eckman, C.; Hardy, J.; Hutton, M.; McGowan, E. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001, 293, 1487-1491.
237. Perez, M.; Ribe, E.; Rubio, A.; Lim, F.; Moran, M.A.; Ramos, P. G.; Ferrer, I.; Isla, M. T.; Avila, J. Characterization of a double (amyloid precursor protein-tau) transgenic: tau phosphorylation and aggregation. Neuroscience 2005, 130, 339-347.
238. Ribe, E. M.; Perez, M.; Puig, B.; Gich, I.; Lim, F.; Cuadrado, M.; Sesma, T.; Catena, S.; Sanchez, B.; Nieto, M.; Gomez-Ramos, P.; Moran, M. A.; Cabodevilla, F.; Samaranch, L.; Ortiz, L.; Perez, A.; Ferrer, I.; Avila, J.; Gomez-Isla, T. Accelerated amyloid d eposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol. Dis. 2005, 20, 814-822.