Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats

Alzheimer's disease (AD) is characterized by increased beta amyloid (Abeta) levels, extracellular Abeta deposits in senile plaques, neurofibrillary tangles, and neuronal loss. However, the physiological role of normal levels of Abeta and its parent protein, the amyloid precursor protein (APP) a...

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Published in:Molecular medicine (Cambridge, Mass.) Mass.), 2004-01, Vol.10 (1-6), p.36-44
Main Authors: Ruiz-Opazo, Nelson, Kosik, Kenneth S, Lopez, Lyle V, Bagamasbad, Pia, Ponce, Lorenz Rb, Herrera, Victoria Lm
Format: Article
Language:English
Subjects:
Aging
Alzheimer Disease - etiology
Alzheimer Disease - metabolism
Amyloid beta-Peptides - analysis
Amyloid beta-Peptides - biosynthesis
Amyloid beta-Protein Precursor - biosynthesis
Amyloid beta-Protein Precursor - genetics
Animals
Animals, Genetically Modified
Brain - metabolism
Brain - physiopathology
Cognition - physiology
Food Preferences - physiology
Hippocampus - physiology
Male
Maze Learning - physiology
Memory - physiology
Mutation
Rats
Rats, Inbred F344
Rats, Sprague-Dawley
RNA, Messenger - biosynthesis
Spatial Behavior - physiology
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Summary:Alzheimer's disease (AD) is characterized by increased beta amyloid (Abeta) levels, extracellular Abeta deposits in senile plaques, neurofibrillary tangles, and neuronal loss. However, the physiological role of normal levels of Abeta and its parent protein, the amyloid precursor protein (APP) are unknown. Here we report that low-level transgenic (Tg) expression of the Swedish APP mutant gene (APPswe) in Fischer-344 rats results in attenuated age-dependent cognitive performance decline in 2 hippocampus-dependent learning and memory tasks compared with age-matched nontransgenic Fischer-344 controls. TgAPPswe rats exhibit mild increases in brain APP mRNA (56.8%), Abeta-42 (21%), and Abeta-40 (6.1%) peptide levels at 12 mo of age, with no extracellular Abeta deposits or senile plaques at 6, 12, and 18 mo of age, whereas 3- to 6-fold increases in Abeta levels are detected in plaque-positive human AD patients and transgenic mouse models. The data support the hypothesis that a threshold paradigm underlies Abeta-related pathology, below which APP expression may play a physiological role in specific hippocampus-dependent tasks, most likely related to its neurotrophic role.
ISSN:1076-1551
1528-3658
DOI:10.2119/2003-00044.Herrera