title: Proliferation, differentiation and amyloid-β production in neural progenitor cells isolated from TgCRND8 mice.
abstract: The amyloid precursor protein (APP) and amyloid-β (Aβ) peptide play central roles in the pathology and etiology of Alzheimer's disease. Amyloid-induced impairments in neurogenesis have been investigated in several transgenic mouse models but the mechanism of action remains to be conclusively demonstrated. The changes in neurogenesis during this transition of increasing Aβ levels and plaque formation were investigated in the present study. We found that the proliferation of newborn cell in the dentate gyrus was enhanced prior to elevations in soluble Aβ production as well as amyloid deposition in 5-week-old TgCRND8 mice, which are well-established Alzheimer's disease models, compared to non-transgenic (Non-Tg) mice. The number of BrdU-positive cells remained higher in TgCRND8 vs Non-Tg mice for a period of 8weeks. The numbers of BrdU/NeuN-positive cells were not significantly different in TgCRND8 compared to Non-Tg mice. A significant decrease in BrdU/GFAP but not in BrdU/S100β was found in Tg vs Non-Tg at 6-weeks of age. In addition, a unique observation was made using isolated neuroprogenitor cells from TgCRND8 mice which were found to be less viable in culture and produced substantial amounts of secreted Aβ peptides. This suggests that the proliferation of neural progenitors in vivo may be modulated by high levels of APP expression and the resulting Aβ generated directly by the progenitor cells. These findings indicate that cell proliferation is increased prior to Aβ deposition and that cell viability is decreased in TgCRND8 mice over time.
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada. Electronic address: soshikanemoto@hiroshima-u.ac.jp.
authors.forename: S
authors.initials: S
authors.lastname: Kanemoto
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Griffin
authors.affiliation: Sunnybrook Research Institute and Department of Laboratory Medicine and Pathobiology, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Markham-Coultes
authors.affiliation: Sunnybrook Research Institute and Department of Laboratory Medicine and Pathobiology, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Aubert
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada; Department of Medicine (Neurology), University of Toronto, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Tandon
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada; Department of Medicine (Neurology), University of Toronto, Canada; Cambridge Institute for Medical Research, Cambridge National Institute of Health Research, Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: P S
authors.initials: PS
authors.lastname: George-Hyslop
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada; Department of Medical Biophysics, University of Toronto, Canada.
authors.forename: P E
authors.initials: PE
authors.lastname: Fraser
mesh_terms: D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D018891:Dentate Gyrus / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein; D006624:Hippocampus / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D064568:S100 Calcium Binding Protein beta Subunit; C579159:S100b protein, mouse; C528900:glial fibrillary astrocytic protein, mouse; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; amyloid; neural progenitor cells; transgenic mice