Neuroscience Laboratory, Research Center, Hospital 12 de Octubre, Madrid, Spain.
Am J Med Genet B Neuropsychiatr Genet. 2010 Jun 5;153B(4):895-902. doi: 10.1002/ajmg.b.31056.
Elevated cerebral levels of amyloid beta-protein (Abeta) occur in Alzheimer's disease (AD), yet only a few patients show evidence of increased Abeta production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Abeta. Megalin, which plays an important role in mediating Abeta clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for AD, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD.
脑内淀粉样β蛋白（Abeta）水平升高发生于阿尔茨海默病（AD），但仅有少数患者表现出 Abeta 产生增加的证据。这一观察结果提示，许多（如果不是大多数）AD 病例是由 Abeta 清除功能缺陷引起的。介导 Abeta 清除的 megalin 是与 AD 遗传关联的一个有吸引力的候选基因。为了研究这一假说，我们在 2183 例人群中分析了 megalin 基因。遗传分析表明，位于 megalin 启动子中的 rs3755166（G/A）多态性与 AD 风险相关，与载脂蛋白 E 基因型无关。AD 患者的 rs3755166 AA 基因型频率明显高于对照组。此外，萤光素酶报告基因检测表明，rs3755166 A 变体的转录活性比 rs3755166 G 变体低 20%。本研究为该 megalin 多态性赋予 AD 更高风险提供了有力证据，并支持 megalin 在 AD 相关神经退行性过程中具有生物学作用。
