Lifespan profiles of Alzheimer's disease-associated genes and products in monkeys and mice.
Lifespan profiles of Alzheimer's disease-associated genes and products in monkeys and mice.
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DOI：
10.3233/jad-2009-1138
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Lahiri DK
中科院分区：
文献类型：
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作者：
Dosunmu R;Wu J;Adwan L;Maloney B;Basha MR;McPherson CA;Harry GJ;Rice DC;Zawia NH;Lahiri DK
阿尔茨海默病（Alzheimer's disease，AD）是一种以β淀粉样蛋白（amyloid-β precursor protein，AβPP）裂解而成的β淀粉样蛋白（amyloid-β，Aβ）肽斑块为特征的疾病。我们的假设是，AD相关的mRNA和蛋白质水平在猴子的寿命谱将不同于小鼠，并且差异的寿命表达谱将有助于了解人类AD的发病机制。我们比较了啮齿类和灵长类动物中AβPP mRNA、AβPP蛋白和Aβ水平的谱。我们还追踪了AβPP基因的转录调节因子特异性蛋白1（SP1）和β淀粉样蛋白前体裂解酶（BACE 1）。在小鼠中，AβPP和Sp1 mRNA及其蛋白产物在生命后期升高; Aβ水平在老年时下降。在猴子中，Sp1、AβPP和BACE 1 mRNA在老年时下降，而蛋白质产物和Aβ水平上升。两个物种中的蛋白水解加工与Aβ的产生不匹配。在灵长类动物中，AβPP和Sp1 mRNA水平协调，但与相应的蛋白质产物以及Aβ水平存在反比关系。人类DNA和mRNA序列与猴和小鼠对应物的比较揭示了可能解释转录和翻译加工差异的结构特征。这些发现对于选择AD和其他年龄相关疾病的适当模型非常重要。
Alzheimer's disease (AD) is characterized by plaques of amyloid–beta (Aβ) peptide, cleaved from amyloid–β precursor protein (AβPP). Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice, and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AβPP mRNA, AβPP protein, and Aβ levels in rodents and primates. We also tracked a transcriptional regulator of the AβPP gene, specificity protein 1 (SP1), and the β amyloid precursor cleaving enzyme (BACE1). In mice, AβPP and Sp1 mRNA and their protein products were elevated late in life; Aβ levels declined in old age. In monkeys, Sp1, AβPP, and BACE1 mRNA declined in old age, while protein products and Aβ levels rose. Proteolytic processing in both species did not match production of Aβ. In primates, AβPP and Sp1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products, as well as Aβ levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age–related diseases.