Proliferation, differentiation and amyloid-β production in neural progenitor cells isolated from TgCRND8 mice

Highlights • In young TgCRND8 mice, proliferation of newborn cells in dentate gyrus is increased, compared with Non-Tg control mice. • On the contrary, differentiation to neural progenitor cells of newborn cells in the TgCRND8 hippocampus is impaired. • Neurosphere cultures isolated from hippocampi of TgCRND8 mice show low viability than those from Non-Tg control. • Neurosphere cultures from TgCRND8 mice secrete high levels of Aβ peptide.
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 8 weeks. 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.