Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress

• Published in: Neuroscience 2004, Vol.127 (3), p.601-609
• Main Authors: Dong, H., Goico, B., Martin, M., Csernansky, C.A., Bertchume, A., Csernansky, J.G.
• Format: Article
• Language: English
• Subjects: Amyloid beta-Protein Precursor - genetics; Amyloidosis - pathology; Amyloidosis - physiopathology; Animals; Biological and medical sciences; Cell Division; cell proliferation; Dentate Gyrus - drug effects; Dentate Gyrus - pathology; Dentate Gyrus - physiopathology; Disease Models, Animal; fluoxetine; Fluoxetine - pharmacology; Fundamental and applied biological sciences. Psychology; hippocampus; isolation stress; Memory - drug effects; Memory - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; neurogenesis; Serotonin Uptake Inhibitors - pharmacology; Social Isolation; Stress, Psychological - drug therapy; Stress, Psychological - pathology; Stress, Psychological - physiopathology; Vertebrates: nervous system and sense organs; β-amyloid plaques
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2004.05.040

Tg2576 transgenic mice (mice overexpressing the “Swedish” mutation in the human amyloid precursor protein 695) demonstrated a decreased capacity for cell proliferation in the dentate gyrus of the hippocampus compared with non-transgenic littermates at 3 months, 6 months and 9 months of age. Isolation stress induced by individually housing each mouse from the time of weaning further decreased hippocampal cell proliferation in Tg2576 mice as well as in non-transgenic littermates at 6 months of age. Decreases in hippocampal cell proliferation in isolated Tg2576 mice were associated with impairments in contextual but not cued memory. Fluoxetine administration increased cell proliferation and improved contextual memory in isolated Tg2576 mice. Further, isolation stress accelerated the age-dependent deposition of β-amyloid 42 plaques in Tg2576 mice. Numerous β-amyloid plaques were found in isolated but not non-isolated Tg2576 mice at 6 months of age. These results suggest that Tg2576 mice, a mouse model of Alzheimer disease, have an impaired ability to generate new cells in the dentate gyrus of the hippocampus and that the magnitude of this impairment can be modulated by behavioral interventions and drugs known to have effects on hippocampal neurogenesis in normal rodents. Unexpectedly, isolation stress also appeared to accelerate the underlying process of β-amyloid plaque deposition in Tg2576 mice. These results suggest that stress may have an impact on the underlying disease process associated with Alzheimer's disease.