APP MRNA DYSREGULATION AND ALZHEIMERS DISEASE

描述AB蛋白在中枢神经系统中的蓄积 仍然是阿尔茨海默病(AD)的标志。AB具有蛋白水解性 从淀粉样前体蛋白(APP)中分离出来，而APP本身就是 在神经元、神经胶质细胞以及可能的外周细胞和组织中过度表达。 唐氏综合征患者携带额外的APP等位基因--过度表达APP M RNA增加1.5-2倍，沉积在胞外AB，必然发展为AD。 最近，一个常染色体显性早发性阿尔茨海默病(EoAD)家系 APP基因转录增加，1.6倍正常，稳定 国家APP基因的表达水平。虽然它仍然存在争议，但APP基因mRNA是 迟发性中枢神经系统神经元中可能过度表达1.2-2倍 AD患者与年龄匹配的对照组比较。因此，APP的mRNA水平 控制它们的细胞机制在阿尔茨海默病中可能很重要 发病机制。申请人最近证明了APP mRNA的稳定性是 受29个碱基，3‘未翻译的调控相互作用的控制 区域不稳定因子和两种信使核糖核酸结合蛋白 HnRNP C蛋白。29个碱基在所有淀粉样变性APP中都存在 MRNAs以及小鼠同系物和静息状态下破坏APP mRNA的稳定性 细胞。在细胞刺激后，核仁素和hnRNP C被激活，结合 APP基因的表达，使其稳定积累。申请人有 还表明，由于变量的不同，APP mRNA含量的微小差异 稳定导致APP产量大幅增加。因此，它是 建议APP mRNA含量适度增加，与之前看到的相当 在DS中，Eoad亲属和一些AD患者可能会对 应用程序生产。申请人提议检验假设： APP产量的增加在一定程度上取决于APP mRNA的稳定性 转角是由29个碱基元素和hnRNP C之间的相互作用控制的 和核仁素。这将通过研究(I)来测试以确定 29个碱基元素的空间组织和核苷酸序列 调控APP mRNA的衰退，(Ii)表征hnRNP C和 核仁被激活以与APP mRNA结合，以及(Iii)确定其作用 APP mRNA稳定性和稳态水平对AP合成的影响。已被占用 总之，这些研究将探讨APP的潜在机制 转录后基因调控及其对APP和AB的影响 制作。

DESCRIPTION The accumulation of AB protein in the central nervous system remains a hallmark of Alzheimer's Disease (AD). AB is proteolytically cleaved from the amyloid precursor protein (APP) which itself is over-expressed in neurons, glia and possibly peripheral cells and tissues. Patients with Down's Syndrome carry an extra APP allele, overexpress APP mRNA by 1.5-2 fold, deposit extracellular AB and inevitably develop AD. Recently, a family with autosomal dominant, early onset AD (EOAD) was identified with increased APP gene transcription and 1.6 fold normal, steady state APP mRNA levels. While it remains controversial, APP gene mRNA is likely over-expressed by 1.2-2 fold in CNS neurons of a subset of late onset AD patients as compared to age matched controls. Therefore, APP mRNA levels and the cellular mechanisms which control them are likely important in AD pathogenesis. The applicant has recently shown that APP mRNA stability is controlled by the regulated interactions of a 29 base, 3' untranslated region destabilizing element and two mRNA binding proteins, nucleolin and hnRNP C protein. The 29 base element is found in all amyloidogenic APP mRNAs as well as the murine homologue and destabilizes APP mRNA in resting cells. After cell stimulation, nucleolin and hnRNP C are activated, bind APP mRNA, causing its stabilization and accumulation. The applicant has also shown that small differences in APP mRNA content due to variable stability cause significant increases in APP production. Therefore, it is proposed that modest increases in APP mRNA content comparable to that seen in DS, an EOAD kindred and some AD patients can have significant effects on APP production. The applicant proposes to test the hypothesis that "increased APP production in part depends on APP mRNA stability which in turn is controlled by interactions between the 29 base element and hnRNP C and nucleolin." This will be tested by the studies (i) to identify the spatial organization and nucleotide sequence of the 29 base element regulating the decay of APP mRNA, (ii) to characterize how hnRNP C and nucleolin are activated to bind to APP mRNA, and (iii) determine the effects of APP mRNA stability and steady state levels on AP synthesis. Taken together, these studies will investigate the underlying mechanisms of APP mRNA posttranscriptional gene regulation and its consequences on APP and AB production.