Epigenetic regulation of sexually divergent neuroinflammation with brain aging and Alzheimer's disease

性别分化神经炎症与大脑衰老和阿尔茨海默病的表观遗传调控

基本信息

批准号：
10220837
负责人：
Sarah Renee Ocanas
金额：
$ 2.66万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2022-05-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220837
关键词：
Address Adult Affinity Chromatography Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Animals Anti-Inflammatory Agents Brain Cell Nucleus Centenarian Characteristics Chronic Cognitive Cognitive deficits Cytosine DNA DNA Methylation DNA Modification Process Data Data Set Development Epigenetic Process Female Future Gene Expression Genome Gliosis Goals Hippocampus (Brain)Home Human Hyperactivity Immunohistochemistry Impaired cognition Incidence Inflammation Inflammatory Infusion procedures Life Messenger RNA Methods Methylation Microglia Modeling Modification Monitor Mus Nerve Degeneration Neurodegenerative Disorders Nucleic Acid Regulatory Sequences Nucleic Acids Pathologic Pathway interactions Pattern Peptides Phenotype Physiological Play Predisposition Process Proteins RNA Regulation Research Training Ribosomes Risk Factors Rodent Model Role Sentinel Sex Differences Stimulus Tamoxifen Therapeutic Intervention Transgenic Animals Transgenic Model Transgenic Organisms Translating Woman abeta oligomer age effect age related aged aging brain bisulfite sequencing cell type chemokine cognitive testing comparative cytokine epigenetic regulation epigenome epigenome editing epigenomics experimental study genomic locus insight lateral ventricle macrophage male neuroinflammation neuropathology neurotoxicity novel prevent response sex therapeutic development transcriptome transcriptomics whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Age and sex are the primary risk factors for developing Alzheimer’s disease (AD), with a higher incidence in women at all ages from 60-100 years old. Mechanisms underlying the cause of sex differences in AD are not well understood, preventing the development of sex-specific therapeutic interventions. Chronic, low-grade inflammation is characteristic of brain aging and neurodegeneration. As the sentinel macrophages of the CNS, microglia play an important role in sensing and responding to changes in the CNS milieu. Microglia monitor the CNS for foreign/’non-self’ and endogenous substances, serving both neuroprotective and neurodegenerative functions. Under normal physiological conditions, microglia retain a relatively quiescent, surveillance phenotype; however stimulation can polarize microglia to the pro-inflammatory M1 phenotype or anti-inflammatory M2 phenotype. Control of microglial phenotypic switching involves regulation of DNA modifications, principally methylation and hydroxymethylation of cytosines, which control genome accessibility and gene expression. Exuberant activation of microglial-specific inflammatory pathways with age in females and sexual divergence in DNA modifications with age point to an epigenetic role in sex differences in brain aging and neuroinflammation. However, paired epigenomic and transcriptomic studies have not been conducted in hippocampal microglia with age between sexes. To address this barrier to progress we developed microglial-specific, tamoxifen-inducible, transgenic NuTRAP models to allow isolation of nucleic acids (DNA & RNA) from lineage-traced microglia. In Aim 1, microglial-specific hippocampal changes in mC/hmC with aging will be examined by whole genome oxidative bisulfite sequencing (WGoxBS). Epigenomic data, and the paired transcriptomic data from the same animals will be used to determine the role of altered modification patterns in age-related changes in gene expression, enrichment of differential modifications in regulatory regions of the genome, and to identify genomic loci for future epigenome editing experiments. Although sexual divergence is documented in some current rodent models of AD, an acknowledged limitation in the field is that transgenic animals develop AD neuropathology at a young age, unlike sporadic AD, which occurs late in life. New AD models like amyloid-beta (Aβ) oligomer infusion allow for examination of AD-related Aβ neuropathology in the context of brain aging and sex effects. In Aim 2, we combine Aβ-oligomer infusion with our novel NuTRAP model to selectively analyze microglial-specific epigenomic and transcriptomic changes in the context of Aβ neurotoxicity. Further, immunohistochemistry and cytokine/chemokine panels are used readouts for gliosis, to assess the effect of aging on Aβ-induced microglial reactivity between sexes. If successful, these studies will provide insights into sexually divergent microglial function with aging and Aβ-related neuropathology and identify targets for development of sex-specific therapeutic interventions. Future studies will also use these findings to examine the regulators of sexual divergence with brain aging.

项目概要/摘要年龄和性别是阿尔茨海默病（AD）的主要危险因素，其中阿尔茨海默病的发病率较高 60-100 岁所有年龄段的女性 AD 性别差异的潜在机制尚不明确。众所周知，阻止了针对性别的慢性、低级别治疗干预措施的发展。炎症是大脑衰老和神经退行性疾病的特征，作为中枢神经系统的前哨巨噬细胞，小胶质细胞在感知和响应中枢神经系统环境的变化方面发挥着重要作用。中枢神经系统负责外来/“非自身”和内源性物质，既具有神经保护作用，又具有神经退行性作用在正常生理条件下，小胶质细胞保持相对静止的监视表型；然而，刺激可以使小胶质细胞极化为促炎 M1 表型或抗炎 M2 表型的控制主要涉及 DNA 修饰的调节。胞嘧啶的甲基化和羟甲基化，控制基因组可及性和基因表达。随着女性年龄的增长和性别差异，小胶质细胞特异性炎症途径的旺盛激活 DNA 随年龄的变化表明表观遗传在大脑衰老和神经炎症中性别差异中的作用。然而，尚未在海马小胶质细胞中进行配对的表观基因组和转录组研究为了解决这一进展障碍，我们开发了小胶质细胞特异性的、他莫昔芬诱导的、转基因 NuTRAP 模型可从谱系追踪的小胶质细胞中分离核酸（DNA 和 RNA）。目标 1，通过全基因组检查 mC/hmC 中小胶质细胞特异性海马随衰老的变化氧化亚硫酸氢盐测序（WGoxBS），以及来自相同的配对转录组数据。动物将被用来确定修饰模式在与年龄相关的基因变化中的作用表达、基因组调控差异修饰的区域富集，以及鉴定基因组尽管在一些当前的啮齿动物中记录了性别差异，但未来表观基因组编辑实验的基因座。 AD 模型，该领域公认的局限性是转基因动物在以下时间发展 AD 神经病理学与散发性 AD 不同，散发性 AD 发生在晚年，新的 AD 模型如β-淀粉样蛋白 (Aβ) 寡聚体。输注可以在大脑衰老和性别影响的背景下检查 AD 相关的 Aβ 神经病理学。目标 2，我们将 Aβ-寡聚物输注与我们的新型 NuTRAP 模型相结合，选择性地分析小胶质细胞特异性 Aβ 神经毒性背景下的表观基因组和转录组变化。细胞因子/趋化因子组用于神经胶质细胞增生的读数，以评估衰老对 Aβ 诱导的小胶质细胞的影响如果成功，这些研究将提供对性别差异小胶质细胞的见解。与衰老和 Aβ 相关的神经病理学发挥作用，并确定性别特异性发育的目标未来的研究还将利用这些发现来检查性调节因素。与大脑老化的差异。