Recent reports have suggested that the reactivation of otherwise transcriptionally silent transposable elements (TEs) might induce brain degeneration, either by dysregulating the expression of genes and pathways implicated in cognitive decline and dementia or through the induction of immune-mediated neuroinflammation resulting in the elimination of neural and glial cells. In the work we present here, we test the hypothesis that differentially expressed TEs in blood could be used as biomarkers of cognitive decline and development of AD. To this aim, we used a sample of aging subjects (age > 70) that developed late-onset Alzheimer’s disease (LOAD) over a relatively short period of time (12–48 months), for which blood was available before and after their phenoconversion, and a group of cognitive stable subjects as controls. We applied our developed and validated customized pipeline that allows the identification, characterization, and quantification of the differentially expressed (DE) TEs before and after the onset of manifest LOAD, through analyses of RNA-Seq data. We compared the level of DE TEs within more than 600,000 TE-mapping RNA transcripts from 25 individuals, whose specimens we obtained before and after their phenotypic conversion (phenoconversion) to LOAD, and discovered that 1790 TE transcripts showed significant expression differences between these two timepoints (logFC ± 1.5, logCMP > 5.3, nominal p value < 0.01). These DE transcripts mapped both over- and under-expressed TE elements. Occurring before the clinical phenoconversion, this TE storm features significant increases in DE transcripts of LINEs, LTRs, and SVAs, while those for SINEs are significantly depleted. These dysregulations end with signs of manifest LOAD. This set of highly DE transcripts generates a TE transcriptional profile that accurately discriminates the before and after phenoconversion states of these subjects. Our findings suggest that a storm of DE TEs occurs before phenoconversion from normal cognition to manifest LOAD in risk individuals compared to controls, and may provide useful blood-based biomarkers for heralding such a clinical transition, also suggesting that TEs can indeed participate in the complex process of neurodegeneration.

最近的报告表明，其他转录沉默的转座因子 (TE) 的重新激活可能会通过失调与认知衰退和痴呆有关的基因和通路的表达或通过诱导免疫介导的神经炎症导致脑退化，从而导致脑退化。神经和胶质细胞。在我们在这里展示的工作中，我们检验了血液中差异表达的 TE 可用作认知衰退和 AD 发展的生物标志物的假设。为此，我们使用了在相对较短的时间内（12-48 个月）发展为迟发性阿尔茨海默病 (LOAD) 的老年受试者（年龄 > 70 岁）样本，在这些受试者出现症状之前和之后都可以获得血液。转换，以及一组认知稳定的受试者作为对照。我们应用了我们开发和验证的定制管道，通过分析 RNA-Seq 数据，可以在明显 LOAD 开始之前和之后识别、表征和量化差异表达 (DE) TE。我们比较了来自 25 个个体的 600,000 多个 TE-mapping RNA 转录本中的 DE TE 水平，我们在他们的表型转换（表型转换）到 LOAD 之前和之后获得了这些个体的样本，发现 1790 个 TE 转录本在这两者之间表现出显着的表达差异时间点（logFC ± 1.5，logCMP > 5.3，标称p值 < 0.01)。这些 DE 转录物映射了过度表达和表达不足的 TE 元素。发生在临床表型转换之前，该 TE 风暴的特点是 LINE、LTR 和 SVA 的 DE 转录本显着增加，而 SINE 的 DE 转录本显着减少。这些失调以明显负荷的迹象结束。这组高度 DE 转录物生成 TE 转录谱，可准确区分这些受试者的表型转换状态之前和之后。我们的研究结果表明，DE TE 风暴发生在pheno之前与对照组相比，风险个体从正常认知转变为表现负荷，并可能提供有用的基于血液的生物标志物来预示这种临床转变，这也表明 TE 确实可以参与神经退行性变的复杂过程。