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Attenuated Hippocampus-Dependent Learning and Memory Decline in Transgenic TgAPPswe Fischer-344 Rats

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Abstract

Alzheimer’s disease (AD) is characterized by increased β amyloid (Aβ) levels, extracellular Aβ deposits in senile plaques, neurofibrillary tangles, and neuronal loss. However, the physiological role of normal levels of Aβ 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%), Aβ-42 (21%), and Aβ-40 (6.1%) peptide levels at 12 mo of age, with no extracellular Aβ deposits or senile plaques at 6, 12, and 18 mo of age, whereas 3- to 6-fold increases in Aβ levels are detected in plaque-positive human AD patients and transgenic mouse models. The data support the hypothesis that a threshold paradigm underlies Aβ-related pathology, below which APP expression may play a physiological role in specific hippocampus-dependent tasks, most likely related to its neurotrophic role.

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Acknowledgments

This work was supported by a grant from the National Institutes of Health, AG16770.

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Authors and Affiliations

  1. Whitaker Cardiovascular Institute, W609, Section of Molecular Medicine, Department of Medicine, Boston University School of Medicine, 700 Albany Street, Boston, Massachusetts, 02118, USA

    Nelson Ruiz-Opazo, Lyle V. Lopez, Pia Bagamasbad, Lorenz R. B. Ponce & Victoria L. M. Herrera

  2. Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave Louis Pasteur Avenue, Boston, Massachusetts, 02115, USA

    Kenneth S. Kosik

Authors
  1. Nelson Ruiz-Opazo
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  2. Kenneth S. Kosik
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  3. Lyle V. Lopez
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  5. Lorenz R. B. Ponce
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  6. Victoria L. M. Herrera
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Correspondence to Victoria L. M. Herrera.

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Ruiz-Opazo, N., Kosik, K.S., Lopez, L.V. et al. Attenuated Hippocampus-Dependent Learning and Memory Decline in Transgenic TgAPPswe Fischer-344 Rats. Mol Med 10, 36–44 (2004). https://doi.org/10.2119/2003-00044.Herrera

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