Evidence supporting a role for the calcium-sensing receptor in Alzheimer disease.
Evidence supporting a role for the calcium-sensing receptor in Alzheimer disease.
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DOI：
10.1002/ajmg.b.30896
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发表时间：
2009-07-05
影响因子：
2.8
通讯作者：
Ferrell, Robert E.
中科院分区：
文献类型：
--
作者：
Conley, Yvette P.;Mukherjee, Ankur;Kammerer, Candace;DeKosky, Steven T.;Kamboh, M. Ilyas;Finegold, David N.;Ferrell, Robert E.
钙敏感受体（CASR）是一种G蛋白偶联的跨膜受体，对Ca 2+水平的变化做出反应。我们假设CASR可能在阿尔茨海默病（AD）中起作用，因为CASR在脑中的表达，钙调节异常促进神经元细胞损伤的易感性的知识，CASR在钙调节中起重要作用，以及AD患者全身钙稳态和G蛋白信号转导改变的事实。为了研究CASR变异与AD易感性的相关性，我们对CASR基因内含子4内的多态性二核苷酸重复标记、启动子区域内的一个SNP和外显子7内的三个非同义SNP进行了基因分型，并使用一组特征良好的AD病例（n = 692）和对照（n = 435）进行了相关性分析。二核苷酸重复序列多态性与AD状态显著相关（OR = 1.62; 95% CI：1.27-2.07，P = 0.00037，Bonferroni校正P = 0.0011），三种非同义SNP单倍型与AD状态呈边缘性相关（P = 0.032，Bonferroni校正P = 0.096）。按APOE 4等位基因携带状态分层显示，仅在非APOE 4携带者中存在显著相关性（OR为1.90; 95%CI：1.37-2.62，P = 0.0001）。我们还研究了apoE或β淀粉样蛋白是否可以激活钙敏感受体。受体激活试验表明，apoE和β淀粉样蛋白激活CASR，并且激活水平似乎依赖于apoE的亚型。这些数据支持我们的假设，即CASR在AD易感性中起作用，特别是在没有APOE 4等位基因的个体中。
The calcium-sensing receptor (CASR) is a G-protein coupled, transmembrane receptor that responds to changes in Ca2+ levels. We hypothesized that the CASR could have a role in Alzheimer disease (AD) given expression of the CASR in brain, knowledge that calcium dysregulation promotes susceptibility to neuronal cell damage, the important role that the CASR plays in calcium regulation, and the fact that systemic calcium homeostasis and G-protein signal transduction are altered in AD patients. To investigate the association of CASR variation in AD susceptibility, we genotyped a polymorphic dinucleotide repeat marker within intron 4, one SNP within the promoter region and three non-synonymous SNPs within exon 7 of the CASR gene and tested for association analysis, using a well-characterized cohort of AD cases (n = 692) and controls (n = 435). The dinucleotide repeat polymorphism was significantly associated with AD status (OR = 1.62; 95% CI: 1.27–2.07, P = 0.00037, Bonferroni corrected P = 0.0011) and the three non-synonymous SNP haplotype was boarderline associated with AD status (P = 0.032, Bonferroni corrected P = 0.096). Stratifying by APOE4 allele carrier status revealed that the significant association was only in non-APOE4 carriers (OR of 1.90; 95% CI: 1.37–2.62, P = 0.0001). We also investigated whether apoE or βamyloid could activate the calcium-sensing receptor. The receptor activation assays revealed that apoE as well as βamyloid activated the CASR and that the level of activation appeared to be isoform dependent for apoE. These data support our hypothesis that the CASR has a role in AD susceptibility, particularly in individuals without an APOE4 allele.
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影响因子：
5.8
作者：
Scillitani, A;Guarnieri, V;Cole, DEC
通讯作者：
Cole, DEC
影响因子：
3.8
作者：
Cole, DEC;Vieth, R;Rubin, LA
通讯作者：
Rubin, LA
DOI：
10.1073/pnas.90.20.9649
发表时间：
1993-10-15
影响因子：
11.1
作者：
SCHMECHEL, DE;SAUNDERS, AM;ROSES, AD
通讯作者：
ROSES, AD
影响因子：
4.2
作者：
Chattopadhyay, Naibedya;Espinosa-Jeffrey, Araceli;de Vellis, Jean
通讯作者：
de Vellis, Jean
影响因子：
9.9
作者：
MCKHANN, G;DRACHMAN, D;STADLAN, EM
通讯作者：
STADLAN, EM