 |
||||
|
||||
|
||||
|
||||
Previous Article | Next Article
Volume 16, Number 21, Issue of November 1, 1996 pp. 6732-6741
Copyright ©1996 Society for NeuroscienceAge-Dependent Neuronal and Synaptic Degeneration in Mice Transgenic for the C Terminus of the Amyloid Precursor Protein
Received May 5, 1996; revised July 23, 1996; accepted Aug. 16, 1996.
Mary Lou Oster-Granite1, Donna L. McPhie2, Jane Greenan1, and Rachael L. Neve2 1 Division of Biomedical Sciences, University of California, Riverside, California 92521-0121, and 2 Department of Genetics, Harvard Medical School and McLean Hospital, Belmont, Massachusetts 02178
The molecular basis for the degeneration of neurons and the deposition of amyloid in plaques and in the cerebrovasculature in Alzheimer's disease (AD) is incompletely understood. We have proposed that one molecule common to these abnormal processes is a fragment of the Alzheimer amyloid precursor protein (APP) comprising the C-terminal 100 amino acids of this molecule (APP-C100). We tested this hypothesis by creating transgenic mice expressing APP-C100 in the brain. We report here that aging (18-28 month) APP-C100 transgenic mice exhibit profound degeneration of neurons and synapses in Ammon's horn and the dentate gyrus of the hippocampal formation. Of the 106 transgenic mice between 8 and 28 months of age that were examined, all of those older than 18 months displayed severe hippocampal degeneration. The numerous degenerating axonal profiles contained increased numbers of neurofilaments, whorls of membrane, and accumulations of debris resembling secondary lysosomes near the cell body. The dendrites of degenerating granule and pyramidal cells contained disorganized, wavy microtubules. Cerebral blood vessels had thickened refractile basal laminae, and microglia laden with debris lay adjacent to larger venous vessels. Mice transgenic for Flag-APP-C100 (in which the hydrophilic Flag tag was fused to the N terminus of APP-C100) showed a similar degree of neurodegeneration in the hippocampal formation as early as 12 months of age. The 45 control mice displayed only occasional necrotic cells and no extensive cell degeneration in the same brain regions. These findings show that APP-C100 is capable of causing some of the neuropathological features of AD.
Key words: Alzheimer's disease; amyloid; neurodegeneration; hippocampus; Flag tag; aging
This article has been cited by other articles:
E. Rockenstein, M. Mante, M. Alford, A. Adame, L. Crews, M. Hashimoto, L. Esposito, L. Mucke, and E. Masliah
High {beta}-Secretase Activity Elicits Neurodegeneration in Transgenic Mice Despite Reductions in Amyloid-{beta} Levels: IMPLICATIONS FOR THE TREATMENT OF ALZHEIMER DISEASE
J. Biol. Chem., September 23, 2005; 280(38): 32957 - 32967.
[Abstract] [Full Text] [PDF]
M. A. Charles, H. Suh, T. A. Hjalt, J. Drouin, S. A. Camper, and P. J. Gage
PITX Genes Are Required for Cell Survival and Lhx3 Activation
Mol. Endocrinol., July 1, 2005; 19(7): 1893 - 1903.
[Abstract] [Full Text] [PDF]
V. Beglopoulos, X. Sun, C. A Saura, C. A. Lemere, R. D. Kim, and J. Shen
Reduced {beta}-Amyloid Production and Increased Inflammatory Responses in Presenilin Conditional Knock-out Mice
J. Biol. Chem., November 5, 2004; 279(45): 46907 - 46914.
[Abstract] [Full Text] [PDF]
R. A. Nixon
Niemann-Pick Type C Disease and Alzheimer's Disease: The APP-Endosome Connection Fattens Up
Am. J. Pathol., March 1, 2004; 164(3): 757 - 761.
[Abstract] [Full Text] [PDF]
L.-W. Jin, I. Maezawa, I. Vincent, and T. Bird
Intracellular Accumulation of Amyloidogenic Fragments of Amyloid-{beta} Precursor Protein in Neurons with Niemann-Pick Type C Defects Is Associated with Endosomal Abnormalities
Am. J. Pathol., March 1, 2004; 164(3): 975 - 985.
[Abstract] [Full Text] [PDF]
Y.-H. Suh and F. Checler
Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease
Pharmacol. Rev., September 1, 2002; 54(3): 469 - 525.
[Abstract] [Full Text] [PDF]
H. Taru, Y. Kirino, and T. Suzuki
Differential Roles of JIP Scaffold Proteins in the Modulation of Amyloid Precursor Protein Metabolism
J. Biol. Chem., July 19, 2002; 277(30): 27567 - 27574.
[Abstract] [Full Text] [PDF]
M. P. Mattson, S. L. Chan, and W. Duan
Modification of Brain Aging and Neurodegenerative Disorders by Genes, Diet, and Behavior
Physiol Rev, July 1, 2002; 82(3): 637 - 672.
[Abstract] [Full Text] [PDF]
J.-H. Kim, J.-C. Rah, S. P. Fraser, K.-A Chang, M. B. A. Djamgoz, and Y.-H. Suh
Carboxyl-terminal Peptide of beta -Amyloid Precursor Protein Blocks Inositol 1,4,5-Trisphosphate-sensitive Ca2+ Release in Xenopus laevis Oocytes
J. Biol. Chem., May 31, 2002; 277(23): 20256 - 20263.
[Abstract] [Full Text] [PDF]
Y. Gao and S. W. Pimplikar
The gamma -secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus
PNAS, December 6, 2001; (2001) 261463298.
[Abstract] [Full Text] [PDF]
H.-S. KIM, C. H. PARK, S. H. CHA, J.-H. LEE, S. LEE, Y. KIM, J.-C. RAH, S.-J. JEONG, and Y.-H. SUH
Carboxyl-terminal fragment of Alzheimer's APP destabilizes calcium homeostasis and renders neuronal cells vulnerable to excitotoxicity
FASEB J, August 1, 2000; 14(11): 1508 - 1517.
[Abstract] [Full Text]
G. Emilien, J.-M. Maloteaux, K. Beyreuther, and C. L. Masters
Alzheimer Disease: Mouse Models Pave the Way for Therapeutic Opportunities
Arch Neurol, February 1, 2000; 57(2): 176 - 181.
[Abstract] [Full Text] [PDF]
D. Moechars, I. Dewachter, K. Lorent, D. Reverse, V. Baekelandt, A. Naidu, I. Tesseur, K. Spittaels, C. V. D. Haute, F. Checler, et al.
Early Phenotypic Changes in Transgenic Mice That Overexpress Different Mutants of Amyloid Precursor Protein in Brain
J. Biol. Chem., March 5, 1999; 274(10): 6483 - 6492.
[Abstract] [Full Text] [PDF]
J. D. Buxbaum, G. Thinakaran, V. Koliatsos, J. O'Callahan, H. H. Slunt, D. L. Price, and S. S. Sisodia
Alzheimer Amyloid Protein Precursor in the Rat Hippocampus: Transport and Processing through the Perforant Path
J. Neurosci., December 1, 1998; 18(23): 9629 - 9637.
[Abstract] [Full Text] [PDF]
L.-W. Jin, M. G. Hearn, C. E. Ogburn, N. Dang, D. Nochlin, W. C. Ladiges, and G. M. Martin
Transgenic Mice Over-Expressing the C-99 Fragment of ßPP with an {alpha}-Secretase Site Mutation Develop a Myopathy Similar to Human Inclusion Body Myositis
Am. J. Pathol., December 1, 1998; 153(6): 1679 - 1686.
[Abstract] [Full Text] [PDF]
A. Popa-Wagner, E. Schroder, L.C. Walker, C. Kessler, and N. Futrell
ß-Amyloid Precursor Protein and ß-Amyloid Peptide Immunoreactivity in the Rat Brain After Middle Cerebral Artery Occlusion : Effect of Age • Editorial Comment: Effect of Age
Stroke, October 1, 1998; 29(10): 2196 - 2202.
[Abstract] [Full Text] [PDF]
K. S. Ermekova, N. Zambrano, H. Linn, G. Minopoli, F. Gertler, T. Russo, and M. Sudol
The WW Domain of Neural Protein FE65 Interacts with Proline-rich Motifs in Mena, the Mammalian Homolog of Drosophila Enabled
J. Biol. Chem., December 26, 1997; 272(52): 32869 - 32877.
[Abstract] [Full Text] [PDF]
D. L. McPhie, R. K. K. Lee, C. B. Eckman, D. H. Olstein, S. P. Durham, D. Yager, S. G. Younkin, R. J. Wurtman, and R. L. Neve
Neuronal Expression of beta -Amyloid Precursor Protein Alzheimer Mutations Causes Intracellular Accumulation of a C-terminal Fragment Containing Both the Amyloid beta and Cytoplasmic Domains
J. Biol. Chem., October 3, 1997; 272(40): 24743 - 24746.
[Abstract] [Full Text] [PDF]
Y. H. Chong, J. H. Sung, S. A. Shin, J.-H. Chung, and Y.-H. Suh
Effects of the beta -Amyloid and Carboxyl-terminal Fragment of Alzheimer's Amyloid Precursor Protein on the Production of the Tumor Necrosis Factor-alpha and Matrix Metalloproteinase-9 by Human Monocytic THP-1
J. Biol. Chem., June 22, 2001; 276(26): 23511 - 23517.
[Abstract] [Full Text] [PDF]
Y. Gao and S. W. Pimplikar
The gamma -secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus
PNAS, December 18, 2001; 98(26): 14979 - 14984.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|