Redefining the Role of APOE RNA Transcripts in Alzheimer's Disease

载脂蛋白E基因（APOE）具有三种遗传变体（即，ε2、ε3和ε4），以及 APOE是阿尔茨海默病（AD）最强的遗传危险因素。这意味着，APOE发挥着重要作用， 在AD发展中的作用。APOE基因产物（mRNA和蛋白质）的表达水平是潜在的 候选人可能部分解释APOE在AD中的作用。但关于AD中APOE表达的研究一直是 结果产生了相互矛盾的数据，关于ε4携带者产生的APOE是高还是低没有共识。 mRNA/蛋白质。这些相互矛盾的结果使APOE在肿瘤细胞中表达作用的解释变得模糊不清。 AD.显然，APOE的表达、ε2/ε3/ε4等位基因和AD状态之间存在差异。有必要 更好地了解他们的关系。在我们的初步研究中，我们发现只有一小部分APOE mRNA延伸基因的全长;也就是说，大多数mRNA过早终止并且不能 产生功能性apoE蛋白。我们还检测到APOE RNA中存在新的环状RNA， 池.这些数据表明，APOE的RNA转录是复杂的， 过去的APOE mRNA表达研究可能存在缺陷， 因为没有测量真正的功能性全长mRNA。解读各种APOE RNA之间的相互作用 转录本，全长mRNA的产生，以及ε2/ε3/ε4等位基因将使我们更好地了解 APOE表达在AD中的作用在这项研究中，我们假设只有一小部分APOE mRNA延长了细胞周期， ε2/ε3/ε4等位基因差异性地调节这些基因的产生。 功能性全长mRNA，从而增加了AD风险的不同影响。我们的长期目标是充分了解 APOE的基因调控，并利用这些知识来制定预防和/或干预AD的策略。 我们的短期目标是阐明载脂蛋白E RNA转录、ε2/ε3/ε4变异体和 AD风险和了解调节APOE RNA产生的分子机制。我们设计了 研究的三个具体目标。目的1将研究APOE RNA，并将其表达水平与 ε2/ε3/ε4等位基因变异与人类死后脑中AD状态的关系。目的2将表征表观遗传 调节人细胞系中APOE RNA转录的机制。目标3将研究函数， 生物起源，以及新发现的APOE环状RNA在人类细胞系和体液中的分布。我们 这项工作将不会削弱apoE蛋白的作用，相反，它将从apoE中分离出apoE RNA的作用 APOE基因在AD中的综合作用。

The apolipoprotein E gene (APOE) has three genetic variants (i.e., ε2, ε3, and ε4), and the ε4 variant of the APOE is the strongest genetic risk factor for Alzheimer's disease (AD). This means that APOE plays a major role in the development of AD. The expression levels of APOE gene products (mRNA and protein) are potential candidates that may partially explain APOE's effects in AD. But studies on APOE expression in AD have always yielded conflicting data, and there is no consensus on whether ε4 carriers produce higher or a lower APOE mRNA/protein. Such conflicting results have significantly obscured interpretation of APOE's expression role in AD. Clearly, gaps exist between APOE's expression, the ε2/ε3/ε4 alleles, and AD status. There is a need for better understanding their relationship. In our preliminary study, we have found that only a fraction of APOE mRNA extends the full length of the gene; that is, the majority of mRNAs are prematurely terminated and cannot produce functional apoE proteins. We have also detected the presence of novel circular RNAs in APOE RNA pools. These data suggest that APOE's RNA transcription is complex and may pose more biological consequences than previously thought; and that past APOE mRNA expression studies may have been flawed for not measuring the true functional full-length mRNA. Deciphering the interplay between various APOE RNA transcripts, the production of full-length mRNA, and the ε2/ε3/ε4 alleles will lead us to better understand the effects of APOE expression in AD. In this study, we hypothesize that only a fraction of APOE mRNA extend the full length of the gene to produce apoE protein; the ε2/ε3/ε4 alleles differentially modulate the production of these functional full-length mRNAs, thereby adding diverse effects to AD risk. Our long-term goal is to fully understand gene regulation of APOE and to use this knowledge to develop strategies for AD prevention and/or intervention. Our short-term goal is to clarify the relationship between APOE RNAs transcription, the ε2/ε3/ε4 variants, and AD risk and to understand the molecular mechanisms that regulate APOE RNAs production. We have designed three specific aims for the study. Aim 1 will investigate APOE RNAs and correlate their expression levels with the ε2/ε3/ε4 allele variants, and AD status in human postmortem brain. Aim 2 will characterize the epigenetic mechanisms that modulate the APOE RNAs transcription in human cell lines. Aim 3 will investigate the function, biogenesis, and distribution of the newly discovered APOE circular RNA in human cell lines and body fluid. Our work will not diminish the role of apoE protein; instead, it will dissect the contributions of APOE RNA from apoE protein to complement APOE gene's comprehensive effects in AD.