Neurogenesis and alterations of neural stem cells in mouse models of cerebral amyloidosis
Neurogenesis and alterations of neural stem cells in mouse models of cerebral amyloidosis
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DOI：
10.2353/ajpath.2008.060520
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发表时间：
2008-06-01
影响因子：
6
通讯作者：
Jucker, Mathias
中科院分区：
文献类型：
--
作者：
Ermini, Florian V.;Grathwohl, Stefan;Jucker, Mathias
阿尔茨海默氏病患者的海马体充满了淀粉样斑块，是为数不多的神经发生在整个成年期持续的部位之一。为了评估淀粉样蛋白β沉积对神经干细胞的影响，在两种淀粉样蛋白前体蛋白（APP）转基因小鼠模型中使用溴脱氧尿苷掺入和双皮质素染色评估海马神经发生。在淀粉样蛋白沉积之前的5个月大的APP 23小鼠中，神经发生相对于野生型对照小鼠没有显示出明显的差异，但是25个月大的淀粉样蛋白沉积APP 23小鼠与对照相比显示出神经发生的显著增加。相比之下，8个月大的淀粉样蛋白沉积APPPS 1小鼠显示与对照组相比神经发生减少。为了研究神经发生的改变是否是淀粉样蛋白诱导的神经干细胞水平变化的结果，APPPS 1小鼠与在中枢神经系统特异性巢蛋白启动子下表达绿色荧光蛋白（GFP）的小鼠杂交。8个月大的nestin-GFP X APPPS 1小鼠表现出静止nestin阳性星形胶质细胞样干细胞的减少，而瞬时扩增祖细胞的数量没有变化。引人注目的是，星形胶质细胞样和瞬时扩增的祖细胞都显示出对嗜酸性淀粉样沉积物的异常形态学反应。在doublecortin阳性的未成熟神经元中不再观察到对淀粉样蛋白的类似反应。结果提供了证据，神经干细胞生物学在淀粉样环境中的破坏和支持的发现，神经发生不同的影响之间的各种转基因小鼠模型的阿尔茨海默氏病。
The hippocampus in Alzheimer's disease is burdened with amyloid plaques and is one of the few locations where neurogenesis continues throughout adult life. To evaluate the impact of amyloid-beta deposition on neural stem cells, hippocampal neurogenesis was assessed using bromodeoxyuridine incorporation and doublecortin staining in two amyloid precursor protein (APP) transgenic mouse models. in 5-month-old APP23 mice prior to amyloid deposition, neurogenesis showed no robust difference relative to wild-type control mice, but 25-month-old amyloid-depositing APP23 mice showed significant increases in neurogenesis compared to controls. In contrast, 8-month-old amyloid-depositing APPPS1 mice revealed decreases in neurogenesis compared to controls. To study whether alterations in neurogenesis are the result of amyloid-induced changes at the level of neural stem cells, APPPS1 mice were crossed with mice expressing green fluorescence protein (GFP) under a central nervous system-specific nestin promoter. Eight-month-old nestin-GFP X APPPS1 mice exhibited decreases in quiescent nestin-positive astrocyte-like stem cells, while transient amplifying progenitor cells did not change in number. Strikingly, both astrocyte-like and transient-amplifying progenitor cells revealed an aberrant morphologic reaction toward congophilic amyloid-deposits. A similar reaction toward the amyloid was no longer observed in doublecortin-positive immature neurons. Results provide evidence for a disruption of neural stem cell biology in an amyloidogenic environment and support findings that neurogenesis is differently affected among various transgenic mouse models of Alzheimer's disease.