ncRNAs in plasma EVs of AD patients and their discriminatory power as biomarkers

阿尔茨海默病是痴呆症中最常见、对经济影响最大的一种。 已经建立了基于脑脊液和血液的方法来测量水平 淀粉样β蛋白和过度磷酸化tau有助于AD的早期诊断或监测 治疗的效果和疾病的进展。血浆细胞外小泡(EVS)和 他们的货物提供了分离和分析与人类相关的分子的机会 病理情况。我们最近发现了小核仁非编码RNA (SnoRNAs)与非痴呆对照组相比，AD患者血浆EV中的snoRNAs高度丰富。 我们假设tau聚集体不可逆转地结合snoRNA，阻止它们执行其 正常功能导致它们在AD脑中的代偿性表达增加。我们的 假设某些SNORD及其分泌在神经元来源的EVS中的表达是 随着阿尔茨海默病的进展而增加。小的非编码核仁snoRNA可能是理想的 生物标志物，与蛋白质和/或mRNAs相比，因为血浆的保护作用 EV和ddPCR技术前所未有的检测灵敏度-低至单一 成绩单。 该建议的主要目标是：1)测试和验证SNORD115的诊断准确性 和SNORD116在人血浆中的ddPCR检测；2)了解这些关联的性质 在AD血浆EVS中特定SNORD的丰度与它们在大脑中的表达水平之间， 疾病状态和进展，以及是否与载脂蛋白E基因相关；3)检测 关于SNORD丰度变化的表观遗传机制，以及4)使用AD 淀粉样蛋白和tau蛋白聚集对胰岛素样生长因子、脑脊液和血浆血管紧张素转换酶的影响 货物。更好地了解潜在的调控基因组、表观基因组和细胞 阿尔茨海默病患者血浆EVS中SNORDS含量差异的机制 患者与对照组的比较将有助于理解载脂蛋白E介导的风险的基本方面 在AD的诊断和建立可靠的诊断策略方面。

Alzheimer's disease is the most common and economically impactful form of dementia. Approaches based on cerebrospinal fluid and blood have been established to measure the levels of amyloid beta and hyperphosphorylated tau to facilitate early diagnosis of AD or to monitor the effects of therapeutics and progression of the disease. Plasma extracellular vesicles (EVs) and their cargo present an opportunity to isolate and profile molecules associated with human pathological conditions. We have recently discovered small nucleolar non-coding RNAs (snoRNAs) highly enriched in plasma EVs of AD patients compared to non-demented controls. We posit that tau aggregates irreversibly bind snoRNAs preventing them from performing their normal function resulting in a compensatory increase of their expression in AD brains. Our hypothesis is that the expression of certain SNORDs and their secretion in neuron derived EVs is increased with the progression of AD. Small non-coding nucleolar snoRNAs might represent ideal biomarkers, compared with proteins and/or mRNAs, because of the protective effect of plasma EV and the unprecedented sensitivity of detection by ddPCR technology – down to single transcripts. This proposal's primary goals are: 1) to test and validate the diagnostic accuracy of SNORD115 and SNORD116 ddPCR assays in human plasma; 2) to understand the nature of the associations between the abundance of particular SNORDs in AD plasma EVs, their expression level in brain, the disease state and progression, and if there is an association with APOE genotype; 3) to test for epigenetic mechanisms underlying the changes in abundance of SNORDs, and 4) using AD mouse models to reveal the effect of amyloid and tau aggregation on ISF, CSF and plasma EVs cargo. A better understanding of the underlying regulatory genomic, epigenomic, and cellular mechanisms responsible for the differences in the enrichment of SNORDs in plasma EVs of AD patients compared to Controls would help understand essential aspects of APOE mediated risk of AD and in establishing reliable diagnostic strategies.