Tang Jun, Song Min, Wang Yanyan, Fan Xiaotang, Xu Haiwei, Bai Yun
Department of Medical Genetics, Third Military Medical University, Chongqing 400038, PR China; Department of Physiology, Third Military Medical University, Chongqing 400038, PR China.
Biochem Biophys Res Commun. 2009 Jul 31;385(3):341-5. doi: 10.1016/j.bbrc.2009.05.067. Epub 2009 May 20.
In addition to the subventricular zone, the dentate gyrus of the hippocampus is one of the few brain regions in which neurogenesis continues into adulthood. Perturbation of neurogenesis can alter hippocampal function, and previous studies have shown that neurogenesis is dysregulated in Alzheimer disease (AD) brain. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin have been shown to play important roles both in embryonic development and in the adult nervous system, and may regulate hippocampal neurogenesis. Previous data indicated that increased expression of BMP4 mRNA within the dentate gyrus might contribute to decreased hippocampal cell proliferation in the APP(swe)/PS1(DeltaE9) mouse AD model. However, it is not known whether the BMP antagonist Noggin contributes to the regulation of neurogenesis. We therefore studied the relative expression levels and localization of BMP4 and its antagonist Noggin in the dentate gyrus and whether these correlated with changes in neurogenesis in 6-12 mo old APP(swe)/PS1(DeltaE9) transgenic mice. Bromodeoxyuridine (BrdU) was used to label proliferative cells. We report that decreased neurogenesis in the APP/PS1 transgenic mice was accompanied by increased expression of BMP4 and decreased expression of Noggin at both the mRNA and protein levels; statistical analysis showed that the number of proliferative cells at different ages correlated positively with Noggin expression and negatively with BMP4 expression. Intraventricular administration of a chimeric Noggin/Fc protein was used to block the action of endogenous BMP4; this resulted in a significant increase in the number of BrdU-labeled cells in dentate gyrus subgranular zone and hilus in APP/PS1 mice. These results suggest that BMP4 and Noggin co-modulate neurogenesis.
除了脑室下区，海马体的齿状回是少数几个神经发生持续到成年期的脑区之一。神经发生的扰动会改变海马体功能，先前的研究表明，阿尔茨海默病（AD）脑内神经发生失调。骨形态发生蛋白-4（BMP4）及其拮抗剂Noggin已被证明在胚胎发育和成年神经系统中都发挥着重要作用，并且可能调节海马体神经发生。先前的数据表明，齿状回内BMP4 mRNA表达增加可能导致APP（swe）/PS1（DeltaE9）小鼠AD模型中海马体细胞增殖减少。然而，尚不清楚BMP拮抗剂Noggin是否参与神经发生的调节。因此，我们研究了6至12月龄APP（swe）/PS1（DeltaE9）转基因小鼠齿状回中BMP4及其拮抗剂Noggin的相对表达水平和定位，以及这些是否与神经发生的变化相关。使用溴脱氧尿苷（BrdU）标记增殖细胞。我们报告，APP/PS1转基因小鼠神经发生减少伴随着BMP4 mRNA和蛋白质水平的表达增加以及Noggin表达减少；统计分析表明，不同年龄的增殖细胞数量与Noggin表达呈正相关，与BMP4表达呈负相关。脑室内注射嵌合Noggin/Fc蛋白以阻断内源性BMP4的作用；这导致APP/PS1小鼠齿状回颗粒下区和齿状回门中BrdU标记细胞数量显著增加。这些结果表明，BMP4和Noggin共同调节神经发生。
