攜帶APOE 基因的“阿樸脂蛋白E E4” (APOE4) 等位基因的個(gè)體比攜帶其他變體的個(gè)體患晚發(fā)性阿爾茨海默氏癥的可能性要大十倍,，并且發(fā)病時(shí)間還可能要早一些。Asa Abeliovich及其同事分析了未受影響的APOE ε4攜帶者和晚發(fā)性阿爾茨海默癥患者的整個(gè)轉(zhuǎn)錄組的大腦皮層基因表達(dá),，發(fā)現(xiàn)攜帶者的基因表達(dá)模式隨著時(shí)間的推移向該疾病患者的基因表達(dá)模式變化,。他們用“差異化共表達(dá)關(guān)聯(lián)網(wǎng)絡(luò)分析”識(shí)別出介導(dǎo)APOE4對(duì)大腦轉(zhuǎn)錄組的影響的候選“主控”節(jié)點(diǎn)基因,。可能性最大的候選基因中有幾個(gè)是淀粉質(zhì)前體蛋白的處理和販運(yùn)的以前已知的或新的調(diào)控因子，其中包括APBA2,、 FYN,、RNF219 和SV2A。而且,，F(xiàn)YN 和RNF219的常見遺傳變體能以依賴于APOE4的方式預(yù)示發(fā)病年齡,。最后，抗癲癇藥物SV2A抑制劑“左乙拉西坦”被發(fā)現(xiàn)在從APOE4攜帶者培養(yǎng)出的細(xì)胞中抑制APP處理,，這是值得進(jìn)一步研究的一種相互作用,。
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.
