Polymorphism in genes involved in adrenergic signaling associated with Alzheimer's
Polymorphism in genes involved in adrenergic signaling associated with Alzheimer's
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DOI：
10.1016/j.neurobiolaging.2003.10.006
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发表时间：
2004-08-01
影响因子：
4.2
通讯作者：
Valdivieso, F
中科院分区：
文献类型：
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作者：
Bullido, MJ;Ramos, MC;Valdivieso, F
为了研究肾上腺素能信号在阿尔茨海默病（AD）发病机制中的潜在参与，我们对启动级联反应的基因进行了遗传和功能研究。我们选择了两个功能性单核苷酸多态性（SNPs）在β 1-肾上腺素受体（ADRBI）和G蛋白β 3亚基（GNB 3）基因，分别，并分析其等位基因频率在AD的病例对照样本。我们发现GNB 3 T等位基因在ADRB 1 C等位基因纯合子个体中产生显著的AD风险，表明两种多态性的联合作用影响AD易感性。有趣的是，与GNB 3 C和ADRBI G相比，GNB 3 T和ADRBI C等位基因的共表达在肾上腺素能刺激转染的人细胞系后产生了增加的cAMP水平和MAPK激活。此外，这些等位基因的共表达也产生APP表达的增加。这些数据强烈表明，GNB 3和ADRB 1多态性的组合通过改变细胞对肾上腺素能刺激的反应性产生AD易感性，指出脑肾上腺素能受体的调节是新型AD治疗策略的潜在靶点。(C)2003年爱思唯尔公司All rights reserved.
To investigate the potential involvement of adrenergic signaling in Alzheimer's disease (AD) pathogenesis, we performed genetic and functional studies of genes initiating the cascade. We chose two functional single-nucleotide polymorphisms (SNPs) in the beta1-adrenergic receptor (ADRBI) and the G protein beta3 subunit (GNB3) genes, respectively, and analyzed their allelic frequencies in a case-control sample of AD. We found that the GNB3 T allele produces a significant risk for AD in individuals homozygous for the ADRBI C allele, suggesting that the combined effect of both polymorphisms influences AD susceptibility. Interestingly, the co-expression of GNB3 T and ADRBI C alleles, compared with GNB3 C and ADRBI G, produced increased cAMP levels and MAPK activation following adrenergic stimulation of transfected human cell lines. Furthermore, the co-expression of these alleles also produced increases in APP expression. These data strongly indicate that the combination of GNB3 and ADRBI polymorphisms produces AD susceptibility by changing the cell responsiveness to adrenergic stimulation, pointing to the modulation of brain adrenergic receptors as a potential target for novel AD therapeutic strategies. (C) 2003 Elsevier Inc. All rights reserved.