APP MRNA DYSREGULATION AND ALZHEIMERS DISEASE

描述AB蛋白在中枢神经系统中的积累 仍然是阿尔茨海默病（AD）的标志。 AB蛋白水解 从淀粉样前体蛋白（APP）裂解， 在神经元、神经胶质和可能的外周细胞和组织中过表达。 唐氏综合症患者携带一个额外的APP等位基因，过度表达APP mRNA增加1.5-2倍，存款细胞外AB和不可避免地发展AD。 最近，一个常染色体显性遗传早发性AD（EOAD）家族被发现， 发现APP基因转录增加，是正常的1.6倍，稳定 说明APP mRNA水平。 尽管仍存在争议，但APP基因mRNA 可能在迟发性神经元亚群的CNS神经元中过表达1.2-2倍 AD患者与年龄匹配的对照组相比。 APP mRNA水平 控制它们的细胞机制在AD中可能很重要 发病机制 申请人最近表明，APP mRNA的稳定性是 由一个29个碱基，3'端未翻译的 区域不稳定元件和两个mRNA结合蛋白，核仁素和 hnRNP C蛋白。 29碱基元件存在于所有淀粉样蛋白APP中 mRNA以及鼠同源物，并使APP mRNA不稳定， 细胞 在细胞刺激后，核仁素和hnRNP C被激活， APP mRNA，导致其稳定和积累。 申请人已经 还表明，APP mRNA含量的微小差异，由于变量， 稳定性导致APP产量显著增加。 因此有 提出APP mRNA含量的适度增加与所见的相似， 在DS中，EOAD家族和一些AD患者可能对 APP生产。 申请人提议检验以下假设： “APP产量的增加部分取决于APP mRNA的稳定性， 转角由29碱基与hnRNP C之间的相互作用控制 和核仁素。“这将通过研究进行测试，以确定 29碱基元件的空间结构和核苷酸序列 调节APP mRNA的衰变，（ii）表征hnRNP C和 核仁素被激活以与APP mRNA结合，以及（iii）确定效果 APP mRNA稳定性和稳态水平对AP合成的影响。 采取 总之，这些研究将探讨APP的潜在机制 mRNA转录后基因调控及其对APP和AB的影响 生产

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.