Role of age-dependent repetitive element transcript dysregulation in Alzheimers disease

衰老会增加阿尔茨海默病（AD）的风险，但其潜在机制尚不清楚 明白下一代测序研究（例如，转录组学，RNA-seq）有望识别 脑老化/AD的新介质，但许多人只关注编码基因。所以针对 PAS-19-392，强调“阐明遗传和表观遗传因素，基因组稳定性，损伤， 在这个R 03项目中，我们将探索基因组生物学中的一个新兴课题， 提供对脑老化/AD的新机制的深入了解。具体来说，我们将确定是否与年龄有关的 非编码重复元件（RE）转录本的积累是大脑衰老和 AD，我们将测试相关的治疗策略。我们的理论基础是RE转录本倾向于形成 可能刺激神经炎症的双链RNA（dsRNA）（一种主要的和潜在的靶向 AD机制）。 RE转录物来源于占人类基因组>60%的非编码重复序列。 它们在转录组研究中经常被忽略为“无活性”。然而，越来越多的证据表明， RE的失调/激活直接导致衰老，某些药物干预可能 防止其影响。一些证据还表明，选择RE转录本增加AD，但我们的研究表明， 初步数据显示：a）总体RE转录水平（即，不只是选择RE）， 人外周组织、脑和神经元中的年龄，并且与更大的dsRNA相关; B）相似的RE 在AD患者脑和神经元中，RE转录物和dsRNA增加;和c）RE转录物抑制可 抑制神经炎症信号传导。这些观察结果表明，年龄相关的，全球性的失调， RE转录本可能在脑老化和年龄相关性AD中发挥核心作用，可能是通过引起dsRNA驱动的 神经炎症我们将通过以下方法来研究这种可能性：1）进行大规模的生物信息学分析 多个RNA-seq数据集，以识别与脑相关的关键RE转录物和RE衍生的dsRNA 老化/AD和神经炎症;和2）使用源自人类供体的神经元来测试 减少RE/dsRNA积累以抑制衰老/AD的临床上可转化的植物化学化合物- 相关的神经炎症，并鉴定可能引起神经炎症和AD的RE衍生的dsRNA 通过刺激细胞dsRNA传感器蛋白激酶R（PKR，其已与AD病理学相关联）。 这些研究将为未来的R 01研究提供一个框架， 相关的RE转录物增加有助于脑老化/AD和RE靶向治疗的潜力， 在体内治疗或预防脑老化/AD。

Aging increases the risk for Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. Next-generation sequencing studies (e.g., transcriptomics, RNA-seq) hold promise for identifying novel mediators of brain aging/AD, but many have focused on coding genes only. Therefore, in response to PAS-19-392, which emphasizes the “elucidation of genetic and epigenetic factors, genome stability, damage, and DNA repair” in AD, in this R03 project we will explore an emerging topic in genome biology that may provide insight into novel mechanisms of brain aging/AD. Specifically, we will determine if an age-related accumulation of non-coding repetitive element (RE) transcripts is an important link between brain aging and AD, and we will test related therapeutic strategies. Our rationale is that RE transcripts are predisposed to form double-stranded RNA (dsRNA) that may stimulate neuroinflammation (a major and potentially targetable mechanism of AD). RE transcripts are derived from non-coding repetitive sequences that make up >60% of the human genome. They are often ignored in transcriptome studies as “inactive”. However, growing evidence demonstrates that dysregulation/activation of RE contributes directly to aging, and that certain pharmacological interventions may prevent their effects. Some evidence also indicates that select RE transcripts are increased in AD, but our preliminary data show that: a) global RE transcript levels (i.e., not just select RE) increase progressively with age in human peripheral tissues, brains and neurons, and are associated with greater dsRNA; b) similar RE transcripts and dsRNA are increased in AD patient brains and neurons; and c) RE transcript suppression may inhibit neuro-inflammatory signaling. These observations suggest that an age-related, global dysregulation of RE transcripts could play a central role in brain aging and age-related AD, perhaps by causing dsRNA-driven neuroinflammation. We will investigate this possibility by: 1) conducting a large-scale bioinformatics analysis of multiple RNA-seq datasets to identify key RE transcripts and RE-derived dsRNAs associated with brain aging/AD and neuroinflammation; and 2) using neurons derived from human donors to test the efficacy of clinically translatable, phytochemical compounds that reduce RE/dsRNA accumulation for inhibiting age/AD- related neuroinflammation, and to identify the RE-derived dsRNAs that may cause neuroinflammation and AD by stimulating the cellular dsRNA sensor protein kinase R (PKR, which has been linked with AD pathology). These studies will provide a framework for a future R01 investigating the specific mechanisms by which age- related RE transcript increases contribute to brain aging/AD and the potential for RE-targeting therapies to treat or prevent brain aging/AD in vivo.