淀粉样蛋白β不是影响APP小鼠中成体海马神经发生的主要因子

发布时间：2018-05-26 13:59

本文选题：阿尔茨海默症 + β淀粉样蛋白　；参考：《浙江大学》2016年博士论文

【摘要】：在啮齿类动物和其它多数哺乳动物的整个生命历程中,大脑海马齿状回的新生神经元可以持续产生。新产生的神经元可以整合到已经存在的神经环路中,并参与学习记忆和其它认知功能,如情绪调节。以往的研究表明,成体海马新生神经元的产生在多个阿尔茨海默症转基因小鼠模型中都受到损伤。这些转基因小鼠脑中表达大量Ap(amyloid β)的同时,其APP的量也远远高于非转基因的对照小鼠。因此,成体海马神经发生受损是过量Aβ还是过量APP引起的,目前还不清楚。本研究中,我们以成年hAPP-J20和hAPP-I5两个转基因小鼠为研究对象(二者表达相似水平的hAPPmRNA,但脑中Aβ水平相差悬殊),通过BrdU标记、逆转录病毒载体-GFP标记及POMC-GFP和Nestin-GFP报告小鼠等,观察二者海马中新生神经元的生成情况。结果发现在hAPP-I5小鼠中BrdU和NeuN共标记的成熟神经元、Doublecortin(DCX)标记的2-3周未成熟神经元以及BrdU和MCM2标记的增殖细胞均明显少于非转基因对照小鼠,表明过表达野生型hAPP影响成体海马神经发生。同时我们发现hAPP-I5小鼠中BrdU和NeuN共标记的成熟神经元、DCX标记的2-3周未成熟神经元以及BrdU标记的增殖细胞均明显少于hAPP-J20小鼠,表明海马神经发生的多个阶段在hAPP-I5小鼠中比在hAPP-J20小鼠中受到了更大的影响。我们将hAPP-I5小鼠和hAPP-J20小鼠分别与报告基因小鼠POMC-GFP和Nestin-GFP杂交,结果发现hAPP-I5小鼠中GFP+的2-3周未成熟神经元以及神经干细胞均明显少于hAPP-J20小鼠,从而进一步证实,和hAPP-J20小鼠相比,hAPP-I5小鼠海马中神经发生受到了更大程度的抑制。hAPP-I5和hAPP-J20表达相似水平的hAPPmRNA,但hAPP-J20小鼠脑中Aβ的量远远高于hAPP-I5。以上结果提示,Aβ不是APP小鼠中影响成体海马神经发生的主要因素。
[Abstract]:Throughout the life of rodents and most other mammals, new neurons in the dentate gyrus of the brain can be sustained. The newly generated neurons can be integrated into the existing neural loop and participate in learning, memory and other cognitive functions, such as emotion regulation. Previous studies have shown that the generation of adult hippocampal neonate neurons has been damaged in multiple Alzheimer's disease transgenic mice. At the same time, the amount of APP in these transgenic mice was much higher than that in non-transgenic control mice. Therefore, it is not clear whether the damage of adult hippocampal nerve is caused by excessive A 尾 or excessive APP. In this study, we studied two transgenic mice, adult hAPP-J20 and hAPP-I5, which expressed similar levels of hAPP mRNAs, but the levels of A 尾 in the brain were significantly different. BrdU labeling, retrovirus vector GFP labeling, POMC-GFP and Nestin-GFP reporting mice, etc. The formation of newborn neurons in hippocampus was observed. The results showed that the number of immature neurons labeled by BrdU and NeuN and the proliferative cells labeled by BrdU and MCM2 in hAPP-I5 mice were significantly lower than those in non-transgenic control mice. It is suggested that overexpression of wild-type hAPP affects the neurogenesis of adult hippocampus. At the same time, we found that the number of immature neurons labeled by BrdU and NeuN and proliferative cells labeled by BrdU in hAPP-I5 mice were significantly lower than those in hAPP-J20 mice. The results showed that the multiple stages of hippocampal neurogenesis were more affected in hAPP-I5 mice than in hAPP-J20 mice. We hybridized hAPP-I5 mice and hAPP-J20 mice with POMC-GFP and Nestin-GFP, respectively. The results showed that the immature neurons and neural stem cells of GFP in hAPP-I5 mice were significantly lower than those in hAPP-J20 mice. Compared with hAPP-J20 mice, the hippocampal neurogenesis of hAPP-I5 mice was inhibited to a greater extent by hAPP-I5 and hAPP-J20 expression, but the amount of A 尾 in the brain of hAPP-J20 mice was much higher than that of hAPP-I5 mice. These results suggest that A 尾 is not a major factor affecting the development of adult hippocampal nerves in APP mice.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R749.16

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