Changes in monocyte small noncoding RNAs as a predictor of cognitive decline in mild cognitive impairment and Alzheimer's disease

摘要 9/11事件发生20年后，世界贸易中心（WTC）的反应人员显示， 阿尔茨海默病（AD）或AD相关性痴呆（ADRD）的早期征兆。MCI经常 被认为是正常衰老和痴呆症之间的中间阶段;因此它提供了一个机会之窗 了解疾病的发病机制，并确定导致MCI转化为 痴呆表观遗传脆弱性和基因-环境相互作用已被牵连的病因， ADRD。特别地，小的非编码RNA（sncRNA）已被证明是有前途的生物标志物， 提供了对其病理生理学的深入了解。初步研究结果进一步表明，单核细胞亚群 显示了与MCI相关的转录组的最大变化;这与单核细胞在MCI中发挥作用的证据一致。 在通过血液转导介导中枢和外周系统之间的界面中起关键作用 脑屏障尽管如此，目前还没有研究通过sncRNA对表观遗传的调控， 单核细胞亚群可能解释这些变化如何影响下游基因表达和蛋白质 与AD神经病变和疾病进展相关。这项建议是以下列初步调查结果为基础的： 单核细胞转录组，并利用现有的生物库和临床数据，通过评估单核细胞sncRNA 通过smRNA-seq在24个月内在100名应答者的子集中进行。拟议的研究将确定， 单核细胞sncRNA的变化与临床表型的变化相关;并确定基因靶点 单核细胞亚群中sncRNA的表达与脑神经病理学相关。为了加强这一影响， 在一项研究中，包括了一个探索性的目的，通过整合单核细胞sncRNA、mRNA 以及预测临床表型变化的血浆蛋白。这项研究将是第一次审查 单核细胞sncRNA、mRNA和血浆蛋白之间的协同作用在转化为痴呆的个体中。 这项研究的发现将阐明单核细胞反应在疾病进展中的调节，帮助识别 新的基于血液的生物标志物，可以为治疗工作提供信息。

ABSTRACT Twenty years after 9/11, the World Trade Center (WTC) responders show elevated rates mild cognitive impairment (MCI), an early sign of Alzheimer’s disease (AD) or AD-related dementia (ADRD). MCI is often regarded as an intermediate stage between normal aging and dementia; thus it provides a window of opportunity to understand the pathogenesis of the disorder and identify factors that lead to the conversion of MCI to dementia. Epigenetic vulnerability and gene-environment interactions have been implicated in the etiology of ADRD. In particular, small noncoding RNAs (sncRNAs) have been shown to be promising biomarkers and provide insights into its pathophysiology. Preliminary findings further revealed that monocyte subpopulation showed the largest changes in transcriptome associated with MCI; in line with evidence that monocytes play a pivotal role in mediating the interface between central and peripheral systems via transduction through the blood brain barrier. Despite this, there is no study which has investigated the epigenetic regulation by sncRNAs in monocyte subpopulation that may explain how these changes affect downstream gene expression and proteins associated with AD neuropathy and disease progression. This proposal builds on the preliminary findings in monocyte transcriptome and capitalizes on existing biobank and clinical data by evaluating monocyte sncRNA via smRNA-seq in a subset of 100 responders over a 24-month period. The proposed study will determine if changes in monocyte sncRNAs are associated with changes in clinical phenotype; and identify the gene targets of sncRNAs in monocyte subpopulation associated with cerebral neuropathology. To enhance the impact of this study, an exploratory aim is included to identify a multi-omic signature by integrating monocyte sncRNAs, mRNAs and plasma proteins that predicts changes in clinical phenotype. This study would be the first to examine the synergy between monocyte sncRNAs, mRNAs and plasma proteins in individuals converting to dementia. Findings from this study will shed light on regulation of monocyte responses in disease progression, help identify novel blood-based biomarkers that may inform treatment efforts.