MicroRNA expression within neuronal-derived small extracellular vesicles in frontotemporal degeneration.
MicroRNA expression within neuronal-derived small extracellular vesicles in frontotemporal degeneration.
复制标题
额颞变性的神经元衍生的小细胞外囊泡中的microRNA表达。
DOI：
10.1097/md.0000000000030854
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发表时间：
2022-10-07
期刊：
影响因子：
1.6
通讯作者：
中科院分区：
文献类型：
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作者：
microRNA（miRNAs）是一种小的非编码RNA，是基因表达的强大调节因子，可以影响数百个基因的表达。miRNA可以包装在小的细胞外囊泡（SEV）中，并通过神经元和小胶质细胞释放到细胞外空间中，以局部作用以及穿过血脑屏障并全身作用。我们试图了解额颞叶痴呆（FTD）、阿尔茨海默病（AD）和健康衰老之间神经元SEV miRNA表达的差异。从FTD、AD和健康老年受试者中获得血浆，这些受试者根据年龄、性别和人种/种族进行匹配。此外，一部分参与者还提供了配对的脑脊液样本，以比较血浆和脑脊液中的神经元SEV miRNA。使用微分超离心和针对神经元表面标记物L1 CAM的抗体缀合的Dynabeads®分离神经元SEV。进行RNA测序。12例FTD受试者、11例AD受试者和10例健康老年受试者入组研究。与健康对照相比，FTD中SEV miRNA-181 c下调。与健康对照和FTD相比，AD中的miRNA-122和miRNA-3591下调。使用FDR <0.2，在一组AD和FTD参与者中，与血浆相比，仅发现miRNA-21- 5 p在脑脊液中的表达增加。与健康对照相比，FTD中SEV miRNA-181 c显著下调，基于通路分析，其作用可能通过小胶质细胞介导的神经炎症和与TAR DNA结合蛋白43（TDP-43）的相互作用介导。此外，基于通路分析，FOXO和Hippo通路可能是FTD的重要介质。最后，因为在配对样品中血浆和脑脊液之间仅一种SEV miRNA差异表达，所以血浆代表用于研究神经元SEV miRNA的适当生物流体。
MicroRNAs (miRNAs) are small non-coding RNA that are powerful regulators of gene expression and can affect the expression of hundreds of genes. miRNAs can be packed in small extracellular vesicles (SEV) and released into the extracellular space by neurons and microglia to act locally as well as pass through the blood-brain barrier and act systemically. We sought to understand the differences in neuronal SEV miRNA expression between frontotemporal dementia (FTD), Alzheimer’s disease (AD), and healthy aging. Plasma was obtained from FTD, AD, and healthy aging participants that were matched based on age, sex, and race/ethnicity. Additionally, a subset of participants also provided paired cerebrospinal fluid samples to compare neuronal SEV miRNAs in plasma and cerebrospinal fluid. Neuronal SEV were isolated using differential ultracentrifugation and antibody conjugated Dynabeads® for the neuronal surface marker, L1CAM. RNA sequencing was performed. 12 FTD, 11 with AD, and 10 healthy aging participants were enrolled in the study. In FTD, SEV miRNA-181c was downregulated compared to healthy controls. In AD, miRNA-122 and miRNA-3591 were downregulated compared to those in healthy controls and FTD. Using an FDR <0.2, only miRNA-21-5p was found to have increased expression in the cerebrospinal fluid compared to plasma in a group of AD and FTD participants. SEV miRNA-181c is significantly downregulated in FTD compared to healthy controls and may mediate its effects through microglial-directed neuroinflammation and interaction with TAR DNA-binding protein 43 (TDP-43) based on pathway analysis. Additionally, the FOXO and Hippo pathways may be important mediators of FTD, based on pathway analysis. Lastly, because only one SEV miRNA was differentially expressed between the plasma and cerebrospinal fluid in paired samples, plasma represents an appropriate biofluid for studying neuronal SEV miRNA.