Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease
Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease
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DOI：
10.1093/hmg/ddh140
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发表时间：
2004-06-15
影响因子：
3.5
通讯作者：
Quinn, J
中科院分区：
文献类型：
--
作者：
Reddy, PH;McWeeney, S;Quinn, J
阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，其特征是认知功能受损以及大脑皮层和海马中出现 β 淀粉样蛋白 (Abeta) 斑块。我们的目标是确定对 AD 进展中的细胞变化至关重要的基因，特别强调疾病进展早期的变化。我们研究了已建立的淀粉样前体蛋白 (APP) 转基因小鼠模型（Tg2576 小鼠模型）在疾病进展三个阶段的基因表达谱：Abeta 斑块出现之前（2 个月）、之前（5 个月）和之后（18 个月）。使用 cDNA 微阵列技术，我们在三个时间点的每个时间点测量了来自 Tg2576 小鼠和年龄匹配的野生型 (WT) 小鼠大脑皮层的 11 283 个 cDNA 克隆的 mRNA 水平。该基因表达分析显示，与线粒体能量代谢和细胞凋亡相关的基因在 2 个月大的 Tg2576 小鼠中上调，并且相同的基因在 5 月龄和 18 月龄时上调。这些微阵列结果通过RNA印迹分析得到证实。线粒体基因ATPase-6、热休克蛋白86和程序性细胞死亡基因8的原位杂交结果表明，与WT小鼠相比，Tg2576小鼠的海马齿状回颗粒细胞以及海马和大脑皮层的锥体神经元表达上调。双标记原位杂交结果表明，在 Tg2576 小鼠中，只有具有线粒体基因 ATPase-6 的选择性过度表达神经元才会遭受氧化损伤。因此，这些结果表明突变体 APP 和/或 Abeta 的表达会损害线粒体能量代谢，并且线粒体基因的上调是一种补偿反应。这些发现对于理解 AD 中 Abeta 毒性的机制和制定 AD 治疗策略具有重要意义。
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the impairment of cognitive functions and by beta amyloid (Abeta) plaques in the cerebral cortex and the hippocampus. Our objective was to determine genes that are critical for cellular changes in AD progression, with particular emphasis on changes early in disease progression. We investigated an established amyloid precursor protein (APP) transgenic mouse model (the Tg2576 mouse model) for gene expression profiles at three stages of disease progression: long before (2 months of age), immediately before (5 months) and after (18 months) the appearance of Abeta plaques. Using cDNA microarray techniques, we measured mRNA levels in 11 283 cDNA clones from the cerebral cortex of Tg2576 mice and age-matched wild-type (WT) mice at each of the three time points. This gene expression analysis revealed that the genes related to mitochondrial energy metabolism and apoptosis were up-regulated in 2-month-old Tg2576 mice and that the same genes were up-regulated at 5 and 18 months of age. These microarray results were confirmed using northern blot analysis. Results from in situ hybridization of mitochondrial genes-ATPase-6, heat-shock protein 86 and programmed cell death gene 8-suggest that the granule cells of the hippocampal dentate gyrus and the pyramidal neurons in the hippocampus and the cerebral cortex are up-regulated in Tg2576 mice compared with WT mice. Results from double-labeling in situ hybridization suggest that in Tg2576 mice only selective, over-expressed neurons with the mitochondrial gene ATPase-6 undergo oxidative damage. These results, therefore, suggest that mitochondrial energy metabolism is impaired by the expression of mutant APP and/or Abeta, and that the up-regulation of mitochondrial genes is a compensatory response. These findings have important implications for understanding the mechanism of Abeta toxicity in AD and for developing therapeutic strategies for AD.