Vázquez-Higuera José Luis, Mateo Ignacio, Sánchez-Juan Pascual, Rodríguez-Rodríguez Eloy, Pozueta Ana, Infante Jon, Berciano José, Combarros Onofre
Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University Hospital Marqués de Valdecilla (University of Cantabria), Santander, Spain.
Dement Geriatr Cogn Disord. 2009;28(2):116-20. doi: 10.1159/000234913. Epub 2009 Aug 13.
Abnormal tau hyperphosphorylation is one of the central events in the development of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD), and phosphorylation of tau is accelerated by the increase in the level of neuronal cholesterol. Apolipoprotein E (APOE) promotes the neuronal uptake of cholesterol via APOE receptors such as the low-density lipoprotein receptor-related protein 1 (LRP1), and the APOE epsilon4 allele is associated with an increase in NFT burden in AD brain. In a case-control study in 246 AD patients and 237 healthy controls, we examined whether the combined gene effects between tau (intron 9, rs2471738) polymorphism and LRP1 (exon 3, rs1799986) polymorphism might be responsible for susceptibility to AD, independently or in concert with the APOE epsilon4 allele. Subjects carrying both the tau (intron 9, rs2471738) T allele (CT and TT genotypes) and the LRP1 (exon 3, rs1799986) T allele (CT and TT genotypes) had a 6 times higher risk of developing AD than subjects without these risk genotypes (odds ration = 6.20, 95% confidence interval = 1.74-22.05, p = 0.005), and this genetic interaction was observed in either the presence or the absence of the APOE epsilon4 allele. These data suggest that the synergistic effects (epistasis) between tau and LRP1 might modify the risk of AD in an APOE epsilon4 allele-independent fashion.
异常的tau蛋白过度磷酸化是阿尔茨海默病（AD）神经原纤维缠结（NFTs）形成过程中的核心事件之一，并且神经元胆固醇水平的升高会加速tau蛋白的磷酸化。载脂蛋白E（APOE）通过诸如低密度脂蛋白受体相关蛋白1（LRP1）等APOE受体促进神经元对胆固醇的摄取，并且APOEε4等位基因与AD大脑中NFT负担的增加相关。在一项针对246例AD患者和237名健康对照的病例对照研究中，我们研究了tau（内含子9，rs2471738）多态性与LRP1（外显子3，rs1799986）多态性之间的联合基因效应是否独立地或与APOEε4等位基因协同作用导致AD易感性。同时携带tau（内含子9，rs2471738）T等位基因（CT和TT基因型）和LRP1（外显子3，rs1799986）T等位基因（CT和TT基因型）的受试者患AD的风险比没有这些风险基因型的受试者高6倍（优势比 = 6.20，95%置信区间 = 1.74 - 22.05，p = 0.005），并且在存在或不存在APOEε4等位基因的情况下均观察到这种基因相互作用。这些数据表明，tau蛋白和LRP1之间的协同效应（上位性）可能以一种不依赖APOEε4等位基因的方式改变AD风险。
