Age-related repetitive element dysregulation, neuroinflammation and Alzheimer's disease

与年龄相关的重复元件失调、神经炎症和阿尔茨海默病

• 批准号: 10517003
• 负责人: Thomas LaRocca
• 金额: $ 37.61万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517003
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease risk; Astrocytes; Autophagocytosis; Binding; Bioinformatics; Biological; Brain; Cells; Complementary DNA; Data; Data Set; Dependence; Deposition; Development; Diagnostic; Disease; Double-Stranded RNA; Epigenetic Process; Event; Funding; Future; Gene Proteins; Genetic Transcription; Genome; Human; Impairment; Inflammaging; Inflammation; Inflammatory; Innate Immune Response; Lead; Link; Location; Longitudinal Studies; Methylation; Modeling; Multiomic Data; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathologic Processes; Pathology; Pathway interactions; Patients; Phenotype; Pilot Projects; Play; Process; Quality Control; RNA; Repetitive Sequence; Reporting; Research Project Grants; Role; Sampling; Signal Transduction; Stimulator of Interferon Genes; System; Testing; Therapeutic; Tissues; Toxic effect; Transcript; Work; age related; age related neurodegeneration; aged; aging brain; base; bisulfite sequencing; clinically translatable; design; efficacy testing; extracellular vesicles; genome wide methylation; insight; mild cognitive impairment; neuroinflammation; neurotoxic; sensor; systemic inflammatory response; tau Proteins; transcriptome sequencing; whole genome

PROJECT SUMMARY Growing evidence links transposable/repetitive element (RE) transcripts with Alzheimer’s disease (AD), but the underlying mechanisms and disease relevance are unclear. In this project, we will test the hypothesis that the mechanism linking RE with AD is an age-dependent, global RE transcript increase that causes age/AD- related neuroinflammation. Our rationale is that: 1) aging is the key risk factor for AD; 2) RE transcripts derived from structural/retroviral sequences in the genome accumulate progressively with aging; 3) RE transcripts are prone to form double-stranded RNA (dsRNA) and/or complementary DNA (cDNA), both of which can cause neuroinflammation (a major driver of brain aging/AD that precedes pathology); 4) aging and AD are also linked with impairments in epigenetic control (e.g., hypo-methylation, which could facilitate RE transcription) and quality control systems like autophagy that degrade RE transcripts (which could potentiate RE-derived cDNA/dsRNA accumulation). Emerging data even suggest that RE-derived dsRNAs/cDNAs could spread via extracellular vesicles (EVs), a potential non-cell-autonomous explanation for the pathology observed in AD. These observations suggest a model that is highly consistent with the age-dependence of AD, in which global, age-related RE transcript increases lead to RE-derived dsRNAs/cDNAs that drive neuroinflammation and AD. In support of this idea, our preliminary data show that RE transcripts are hypomethylated in AD patients and correlate with neuroinflammation prior to pathology, and that inhibiting RE transcript buildup in human astrocytes/neurons may reduce inflammation. We also find evidence of RE in circulating EVs from AD patients. Based on these observations, we propose to (Aim 1) determine if age- rather than pathology-related RE transcript dysregulation links RE with AD by performing a large bioinformatics analysis of existing RNA-seq data, probing for RE in human/AD brains, and profiling global methylation (whole-genome bisulfite sequencing) in the same brains, as well as in samples from >100 subjects from a longitudinal study on brain aging, neuroinflammation and AD. In parallel (Aim 2), we will use patient-derived astrocytes and neurons to test the efficacy of clinically translatable treatments (e.g., methylation/autophagy activators) that reduce RE-derived dsRNAs and cDNAs for inhibiting age/AD-related neuroinflammation, and we will identify RE that may cause neuroinflammation by binding to cellular dsRNA and cDNA sensors (PKR and cGAS). Finally (Aim 3), we will determine if RE transcripts induce aged/AD-like neuroinflammation and accumulate in EVs in young astrocytes and neurons, and whether these EV-borne RE transcripts cause inflammation/toxicity in other cells. We also will use existing samples (as described above) to determine if RE in EVs are related to markers of systemic inflammation, neuroinflammation and AD in humans. These studies are specifically designed to extend on our ongoing, NIA-funded pilot projects, generate multi-omics data on RE in aging/AD, and to provide a platform for future diagnostics or therapeutics in this context.

项目概要 越来越多的证据将转座/重复元件 (RE) 转录本与阿尔茨海默病 (AD) 联系起来，但是 潜在机制和疾病相关性尚不清楚。在这个项目中，我们将测试以下假设： 将 RE 与 AD 联系起来的机制是一种年龄依赖性的、全局 RE 转录增加，导致年龄/AD- 相关的神经炎症。我们的理由是：1）衰老是AD的关键危险因素； 2）RE转录本衍生 基因组中的结构/逆转录病毒序列随着年龄的增长而逐渐积累； 3) RE 成绩单是 容易形成双链 RNA (dsRNA) 和/或互补 DNA (cDNA)，这两种情况都会导致 神经炎症（病理学之前大脑老化/AD 的主要驱动因素）； 4）衰老和AD也是如此 与表观遗传控制损伤有关（例如，低甲基化，这可能促进 RE 转录） 和质量控制系统，如自噬，可降解 RE 转录本（这可能会增强 RE 衍生的 cDNA/dsRNA 积累）。新出现的数据甚至表明 RE 衍生的 dsRNA/cDNA 可以通过 细胞外囊泡（EV），对 AD 中观察到的病理学的潜在非细胞自主解释。 这些观察结果表明了一个与 AD 的年龄依赖性高度一致的模型，其中全球、 与年龄相关的 RE 转录物增加导致 RE 衍生的 dsRNA/cDNA 驱动神经炎症和 AD。 为了支持这一观点，我们的初步数据表明 AD 患者中 RE 转录物甲基化程度较低，并且 与病理之前的神经炎症相关，并且抑制人类 RE 转录物的积累 星形胶质细胞/神经元可以减轻炎症。我们还在 AD 患者的循环 EV 中发现了 RE 的证据。 基于这些观察，我们建议（目标 1）确定 RE 是否与年龄相关而不是病理相关 通过对现有 RNA-seq 进行大型生物信息学分析，转录失调将 RE 与 AD 联系起来 数据、人类/ AD 大脑中 RE 的探测以及全局甲基化分析（全基因组亚硫酸氢盐测序） 在相同的大脑中，以及来自大脑老化纵向研究的超过 100 名受试者的样本中， 神经炎症和AD。同时（目标 2），我们将使用患者来源的星形胶质细胞和神经元来测试 减少 RE 衍生的临床可转化治疗（例如甲基化/自噬激活剂）的功效 用于抑制年龄/AD 相关神经炎症的 dsRNA 和 cDNA，我们将鉴定可能导致 通过与细胞 dsRNA 和 cDNA 传感器（PKR 和 cGAS）结合来抑制神经炎症。最后（目标 3），我们将 确定 RE 转录物是否会诱导衰老/AD 样神经炎症并在年轻星形胶质细胞的 EV 中积累 和神经元，以及这些 EV 传播的 RE 转录物是否会引起其他细胞的炎症/毒性。我们也 将使用现有样本（如上所述）来确定 EV 中的 RE 是否与系统性标志物相关 人类炎症、神经炎症和 AD。这些研究是专门为扩展我们的研究而设计的 NIA 资助的正在进行的试点项目，生成有关衰老/ AD 中 RE 的多组学数据，并为 未来在这方面的诊断或治疗。