Department of Neurobiology, University of Chicago, 947 E. 58th Street, AB 308, Chicago, IL 60637, USA.
Neurodegener Dis. 2010;7(1-3):46-9. doi: 10.1159/000283482. Epub 2010 Feb 13.
Presenilin 1 (PS1) plays a critical role in neurogenesis both during development and in the adult. We recently reported that ubiquitous expression of familial, early-onset Alzheimer's disease-linked PS1 mutants impairs enrichment-induced proliferation and neurogenesis of hippocampal neural progenitor cells (NPCs) in a non-cell autonomous manner. The impairments in proliferation and neurogenesis are, at least in part, due to alterations in the levels of specific chemokines and growth factors secreted from microglia expressing familial Alzheimer's disease-linked PS1 variants. To test our hypothesis that the fate of hippocampal NPCs in PS1 mutant mice is largely determined by cellular factors produced within the niche itself, we are examining the fate of NPCs from hippocampi of wild-type human PS1 or PS1 mutant mice that are marked with green fluorescent protein and BrdU following transplantation into heterologous hosts. In parallel, we have generated transgenic mice that harbor a transgene encoding the PS1DeltaE9 variant flanked with loxP sites that can be conditionally deleted in a temporal and/or spatial manner using specific cre driver lines. These studies will allow us to assess the contributions of varying cell types within the hippocampal stem cell niche that express mutant PS1 to NPC proliferation and differentiation.
早老素 1（PS1）在神经发生中起着至关重要的作用，无论是在发育过程中还是在成年期。我们最近报道称，家族性早发性阿尔茨海默病相关 PS1 突变体的普遍表达以非细胞自主的方式损害了海马神经祖细胞（NPC）的富集诱导增殖和神经发生。增殖和神经发生的损伤至少部分归因于从小胶质细胞分泌的特定趋化因子和生长因子水平的改变，这些小胶质细胞表达家族性阿尔茨海默病相关 PS1 变体。为了验证我们的假设，即 PS1 突变小鼠中海马 NPC 的命运在很大程度上取决于龛内自身产生的细胞因子，我们正在检查来自野生型人类 PS1 或 PS1 突变小鼠海马 NPC 的命运，这些 NPC 在移植到异源宿主后用绿色荧光蛋白和 BrdU 标记。同时，我们已经生成了携带 PS1DeltaE9 变体的转基因小鼠，该变体侧翼带有 loxP 位点，可以使用特定的 cre 驱动线以时间和/或空间方式条件性删除。这些研究将使我们能够评估表达突变 PS1 的海马干细胞龛内不同细胞类型对 NPC 增殖和分化的贡献。
