携带APOE 基因的“阿朴脂蛋白E E4” (APOE4) 等位基因的个体比携带其他变体的个体患晚发性阿尔茨海默氏症的可能性要大十倍，并且发病时间还可能要早一些。Asa Abeliovich及其同事分析了未受影响的APOE ε4携带者和晚发性阿尔茨海默症患者的整个转录组的大脑皮层基因表达，发现携带者的基因表达模式随着时间的推移向该疾病患者的基因表达模式变化。他们用“差异化共表达关联网络分析”识别出介导APOE4对大脑转录组的影响的候选“主控”节点基因。可能性最大的候选基因中有几个是淀粉质前体蛋白的处理和贩运的以前已知的或新的调控因子，其中包括APBA2、 FYN、RNF219 和SV2A。而且，FYN 和RNF219的常见遗传变体能以依赖于APOE4的方式预示发病年龄。最后，抗癫痫药物SV2A抑制剂“左乙拉西坦”被发现在从APOE4携带者培养出的细胞中抑制APP处理，这是值得进一步研究的一种相互作用。
Nature doi:10.1038/nature12415
Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease
Herve Rhinn, Ryousuke Fujita, Liang Qiang, Rong Cheng, Joseph H. Lee & Asa Abeliovich
Late-onset Alzheimer’s disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E ε4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these—including APBA2, FYN, RNF219 and SV2A—encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD.
