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Science 4 October 1996:
Vol. 274. no. 5284, pp. 99 - 103
DOI: 10.1126/science.274.5284.99
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Reports

Correlative Memory Deficits, Abeta Elevation, and Amyloid Plaques in Transgenic Mice

Karen Hsiao, * Paul Chapman, Steven Nilsen, Chris Eckman, Yasuo Harigaya, Steven Younkin, Fusheng Yang, Greg Cole

Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta -amyloid (Abeta ) precursor protein containing a Lys670 rightarrow  Asn, Met671 rightarrow  Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta (1-40) and a 14-fold increase in Abeta (1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta . The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.

K. Hsiao and S. Nilsen, Department of Neurology, UMHC Box 295, 420 Delaware Street, University of Minnesota, Minneapolis, MN 55455, USA.
P. Chapman, Physiology Unit, University of Wales, Cardiff CF1 3US, UK.
C. Eckman, Y. Harigaya, S. Younkin, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.
F. Yang and G. Cole, GRECC, Veterans Administration Medical Center, Sepulveda, CA 91343, USA, and Departments of Medicine and Neurology, University of California, Los Angeles, CA 91343, USA.
*   To whom correspondence should be addressed.

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G-CSF rescues the memory impairment of animal models of Alzheimer's disease.
K.-J. Tsai, Y.-C. Tsai, and C.-K. J. Shen (2007)
J. Exp. Med. 204, 1273-1280
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Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice.
A. Muhs, D. T. Hickman, M. Pihlgren, N. Chuard, V. Giriens, C. Meerschman, I. van der Auwera, F. van Leuven, M. Sugawara, M.-C. Weingertner, et al. (2007)
PNAS 104, 9810-9815
   Abstract »    Full Text »    PDF »
Amyloid-beta in Alzheimer Disease: The Null versus the Alternate Hypotheses.
H.-g. Lee, X. Zhu, R. J. Castellani, A. Nunomura, G. Perry, and M. A. Smith (2007)
J. Pharmacol. Exp. Ther. 321, 823-829
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Involvement of -site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity.
H. Ma, S. Lesne, L. Kotilinek, J. V. Steidl-Nichols, M. Sherman, L. Younkin, S. Younkin, C. Forster, N. Sergeant, A. Delacourte, et al. (2007)
PNAS 104, 8167-8172
   Abstract »    Full Text »    PDF »
Conformation-sensitive Antibodies against Alzheimer Amyloid-beta by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide.
N. Moretto, A. Bolchi, C. Rivetti, B. P. Imbimbo, G. Villetti, V. Pietrini, L. Polonelli, S. Del Signore, K. M. Smith, R. J. Ferrante, et al. (2007)
J. Biol. Chem. 282, 11436-11445
   Abstract »    Full Text »    PDF »
Lipocalin-type prostaglandin D synthase/beta-trace is a major amyloid beta-chaperone in human cerebrospinal fluid.
T. Kanekiyo, T. Ban, K. Aritake, Z.-L. Huang, W.-M. Qu, I. Okazaki, I. Mohri, S. Murayama, K. Ozono, M. Taniike, et al. (2007)
PNAS 104, 6412-6417
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{beta}-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer's Disease Pathogenesis.
J. Zhao, Y. Fu, M. Yasvoina, P. Shao, B. Hitt, T. O'Connor, S. Logan, E. Maus, M. Citron, R. Berry, et al. (2007)
J. Neurosci. 27, 3639-3649
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Inhibition of Familial Cerebral Amyloid Angiopathy Mutant Amyloid beta-Protein Fibril Assembly by Myelin Basic Protein.
M. D. Hoos, M. Ahmed, S. O. Smith, and W. E. Van Nostrand (2007)
J. Biol. Chem. 282, 9952-9961
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Conditional Neuronal Simian Virus 40 T Antigen Expression Induces Alzheimer-Like Tau and Amyloid Pathology in Mice.
K. H. J. Park, J. L. Hallows, P. Chakrabarty, P. Davies, and I. Vincent (2007)
J. Neurosci. 27, 2969-2978
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Active {beta}-Amyloid Immunization Restores Spatial Learning in PDAPP Mice Displaying Very Low Levels of {beta}-Amyloid.
G. Chen, K. S. Chen, D. Kobayashi, R. Barbour, R. Motter, D. Games, S. J. Martin, and R. G. M. Morris (2007)
J. Neurosci. 27, 2654-2662
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Dominance of Amyloid Precursor Protein Sequence over Host Cell Secretases in Determining beta-Amyloid Profiles Studies of Interspecies Variation and Drug Action by Internally Standardized Immunoprecipitation/Mass Spectrometry.
P. Du, K. M. Wood, M. H. Rosner, D. Cunningham, B. Tate, and K. F. Geoghegan (2007)
J. Pharmacol. Exp. Ther. 320, 1144-1152
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Antibody-Mediated Clearance of Amyloid-{beta} Peptide from Cerebral Amyloid Angiopathy Revealed by Quantitative In Vivo Imaging.
C. M. Prada, M. Garcia-Alloza, R. A. Betensky, S. X. Zhang-Nunes, S. M. Greenberg, B. J. Bacskai, and M. P. Frosch (2007)
J. Neurosci. 27, 1973-1980
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The Tottori (D7N) and English (H6R) Familial Alzheimer Disease Mutations Accelerate Abeta Fibril Formation without Increasing Protofibril Formation.
Y. Hori, T. Hashimoto, Y. Wakutani, K. Urakami, K. Nakashima, M. M. Condron, S. Tsubuki, T. C. Saido, D. B. Teplow, and T. Iwatsubo (2007)
J. Biol. Chem. 282, 4916-4923
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Magnetic Resonance Imaging of Alzheimer's Pathology in the Brains of Living Transgenic Mice: A New Tool in Alzheimer's Disease Research.
C. R. Jack Jr, M. Marjanska, T. M. Wengenack, D. A. Reyes, G. L. Curran, J. Lin, G. M. Preboske, J. F. Poduslo, and M. Garwood (2007)
Neuroscientist 13, 38-48
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The Novel {gamma} Secretase Inhibitor N-[cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) Reduces Amyloid Plaque Deposition without Evidence of Notch-Related Pathology in the Tg2576 Mouse.
J. D. Best, D. W. Smith, M. A. Reilly, R. O'Donnell, H. D. Lewis, S. Ellis, N. Wilkie, T. W. Rosahl, P. A. Laroque, C. Boussiquet-Leroux, et al. (2007)
J. Pharmacol. Exp. Ther. 320, 552-558
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Interferon-{gamma} and Tumor Necrosis Factor-{alpha} Regulate Amyloid-{beta} Plaque Deposition and {beta}-Secretase Expression in Swedish Mutant APP Transgenic Mice.
M. Yamamoto, T. Kiyota, M. Horiba, J. L. Buescher, S. M. Walsh, H. E. Gendelman, and T. Ikezu (2007)
Am. J. Pathol. 170, 680-692
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Learning Decreases A{beta}*56 and Tau Pathology and Ameliorates Behavioral Decline in 3xTg-AD Mice.
L. M. Billings, K. N. Green, J. L. McGaugh, and F. M. LaFerla (2007)
J. Neurosci. 27, 751-761
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A{beta}40 Inhibits Amyloid Deposition In Vivo.
J. Kim, L. Onstead, S. Randle, R. Price, L. Smithson, C. Zwizinski, D. W. Dickson, T. Golde, and E. McGowan (2007)
J. Neurosci. 27, 627-633
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Abeta1-42 stimulates actin polymerization in hippocampal neurons through Rac1 and Cdc42 Rho GTPases.
A. Mendoza-Naranjo, C. Gonzalez-Billault, and R. B. Maccioni (2007)
J. Cell Sci. 120, 279-288
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The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between {beta}-amyloid production and tau phosphorylation in Alzheimer disease.
R. Kimura, K. Kamino, M. Yamamoto, A. Nuripa, T. Kida, H. Kazui, R. Hashimoto, T. Tanaka, T. Kudo, H. Yamagata, et al. (2007)
Hum. Mol. Genet. 16, 15-23
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Insights into the mechanisms of action of anti-A{beta} antibodies in Alzheimer's disease mouse models.
Y. Levites, L. A. Smithson, R. W. Price, R. S. Dakin, B. Yuan, M. R. Sierks, J. Kim, E. McGowan, D. K. Reed, T. L. Rosenberry, et al. (2006)
FASEB J 20, 2576-2578
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Real-time and Single Fibril Observation of the Formation of Amyloid beta Spherulitic Structures.
T. Ban, K. Morigaki, H. Yagi, T. Kawasaki, A. Kobayashi, S. Yuba, H. Naiki, and Y. Goto (2006)
J. Biol. Chem. 281, 33677-33683
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Selective vulnerability of different types of commissural neurons for amyloid {beta}-protein-induced neurodegeneration in APP23 mice correlates with dendritic tree morphology.
E. Capetillo-Zarate, M. Staufenbiel, D. Abramowski, C. Haass, A. Escher, C. Stadelmann, H. Yamaguchi, O. D. Wiestler, and D. R. Thal (2006)
Brain 129, 2992-3005
   Abstract »    Full Text »    PDF »
Therapeutic approaches to Alzheimer's disease.
H.-W. Klafki, M. Staufenbiel, J. Kornhuber, and J. Wiltfang (2006)
Brain 129, 2840-2855
   Abstract »    Full Text »    PDF »


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