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

衰老会增加患阿尔茨海默病(AD)的风险，但其潜在机制尚不清楚 明白了。下一代测序研究(例如，转录学、RNA-SEQ)有望识别 脑老化/阿尔茨海默病的新媒介，但许多只专注于编码基因。因此，为了回应 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AD中，在这个R03项目中，我们将探索基因组生物学中的一个新兴主题，该主题可能 提供对大脑老化/AD的新机制的洞察。具体地说，我们将确定与年龄相关的 非编码重复元件(RE)转录本的积累是大脑老化和 AD，我们将测试相关的治疗策略。我们的理论基础是RE成绩单很容易形成 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的发病机制)。 Re转录本来自非编码重复序列，这些序列构成了人类基因组的60%。 在转录组研究中，它们常常被忽略为“不活跃的”。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 防止它们的影响。一些证据还表明，在AD中，精选的RE转录本增加，但我们的 初步数据显示：a)全球RE转录水平(即，不仅仅是精选RE)随着 人类外周组织、大脑和神经元中的AGE，并与更大的dsRNA相关；b)相似的RE 阿尔茨海默病患者大脑和神经元中转录和dsRNA增加；c)RE转录抑制可能 抑制神经炎症信号。这些观察表明，与年龄相关的、全球范围内的 Re转录本可能在大脑老化和老年性AD中发挥核心作用，可能是通过导致dsRNA驱动 神经炎。我们将通过以下方式调查这种可能性：1)进行大规模生物信息学分析 多个RNA-seq数据集，以识别与大脑相关的关键RE转录本和RE衍生dsRNA 衰老/阿尔茨海默病和神经炎症；2)使用来自人类捐赠者的神经元来测试 临床可翻译的植物化学化合物，减少RE/dsRNA积累，抑制AGE/AD- 相关的神经炎症，并鉴定可能导致神经炎症和AD的RE衍生dsRNA 通过刺激细胞dsRNA传感器蛋白激酶R(PKR，已与AD病理联系在一起)。 这些研究将为未来的R01提供一个框架，以研究年龄- 相关RE转录本的增加有助于脑老化/AD以及RE靶向治疗的可能性 在活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.