A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Curr Alzheimer Res. 2012 Nov;9(9):1030-42. doi: 10.2174/156720512803569028.
Enhancement of neurogenesis and stem cell transplantation are potential therapies for neurodegenerative diseases. In Alzheimer's disease (AD) newborn neural cells and the transplanted cells encounter a diseased brain where the accumulation of toxic amyloid-β (Aβ) peptides disturbs normal functions and interactions of brain cells. In addition, ADlinked mutatations in newborn neurons or autologously transplanted neural progenitor cells (NPCs) are likely to affect the fate of these cells. Here we analyzed the effect of AD-linked APdE9 mutant on NPCs in culture and by isolating NPCs from APdE9 transgenic mice and transplanting them into APdE9 and wild type mouse brain. We show that the brain environment in APdE9 mutant mice reduced astrocytic differentiation but increased the survival and migration of NPCs in vivo. APdE9 mutation of NPCs increased neuronal differentiation also in vitro. Instead extracellular Aβ(42) peptide decreased the survival, neuronal differentiation and migration of NPCs in vitro, whereas Aβ(40) had an opposite effect. NPC transplantation induced brain neurogenesis, which was not altered in Aβ burdened APdE9 brain or by APdE9 mutant in NPCs. Thus, AD-linked mutations in newborn neural cells or NPCs do not compromise the utilization of enhanced neurogenesis or autologous NPC transplantation as potential therapies. The results suggest that combining the treatments resulting in reduced Aβ(42) and enhanced neurogenesis may be one therapeutic approach to be explored in AD.
神经发生和干细胞移植的增强是治疗神经退行性疾病的潜在疗法。在阿尔茨海默病（AD）中，新生神经元和移植细胞会遇到一个患病的大脑，其中积累的有毒淀粉样β（Aβ）肽会干扰脑细胞的正常功能和相互作用。此外，新生神经元或自体移植神经祖细胞（NPC）中的 AD 相关突变可能会影响这些细胞的命运。在这里，我们分析了 AD 相关的 AβdE9 突变对 NPC 在培养中的影响，并通过从 AβdE9 转基因小鼠中分离 NPC 并将其移植到 AβdE9 和野生型小鼠脑中来分析其影响。结果表明，APdE9 突变小鼠的大脑环境降低了星形胶质细胞的分化，但增加了 NPC 的体内存活和迁移。体外的 AβdE9 突变 NPC 也增加了神经元分化。相反，细胞外 Aβ（42）肽降低了 NPC 的存活、神经元分化和迁移，而 Aβ（40）则有相反的作用。NPC 移植诱导了大脑神经发生，而在 Aβ 负担过重的 APdE9 大脑或 NPC 中的 APdE9 突变中，这种神经发生没有改变。因此，新生神经元或 NPC 中的 AD 相关突变不会影响增强神经发生或自体 NPC 移植作为潜在治疗方法的利用。结果表明，结合减少 Aβ（42）和增强神经发生的治疗方法可能是 AD 治疗的一种探索途径。
