Neurogenic responses to amyloid-beta plaques in the brain of Alzheimer’s disease-like transgenic (pPDGF-APPSw,Ind) mice

摘要

Formation and accumulation of amyloid-beta (Aβ) plaques are associated with declined memory and other neurocognitive function in Alzheimer’s disease (AD) patients. However, the effects of Aβ plaques on neural progenitor cells (NPCs) and neurogenesis from NPCs remain largely unknown. The existing data on neurogenesis in AD patients and AD-like animal models remain controversial. For this reason, we utilized the nestin second-intron enhancer controlled LacZ (pNes-LacZ) reporter transgenic mice (pNes-Tg) and Bi-transgenic mice (Bi-Tg) containing both pPDGF-APPSw,Ind and pNes-LacZ transgenes to investigate the effects of Aβ plaques on neurogenesis in the hippocampus and other brain regions of the AD-like mice. We chose transgenic mice at 2, 8 and 12 months of age, corresponding to the stages of Aβ plaque free, plaque onset and plaque progression to analyze the effects of Aβ plaques on the distribution and de novo neurogenesis of (from) NPCs. We demonstrated a slight increase in the number of NPCs in the hippocampal regions at the Aβ plaque free stage, while a significant decrease in the number of NPCs at Aβ plaque onset and progression stages. On the other hand, we showed that Aβ plaques increase neurogenesis, but not gliogenesis from post-mitotic NPCs in the hippocampus of Bi-Tg mice compared with age-matched control pNes-Tg mice. The neurogenic responses of NPCs to Aβ plaques suggest that experimental approaches to promote de novo neurogenesis may potentially improve neurocognitive function and provide an effective therapy for AD.