Neuronal senescence and inflammation in Alzheimer's disease

阿尔茨海默病的神经元衰老和炎症

• 批准号: 10633023
• 负责人: FRED H GAGE
• 金额: $ 7.45万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10633023
• 关键词: ATAC-seq; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Astrocytes; Biology; Brain; CDKN2A gene; CSF1 gene; Cell Aging; Cell Proliferation; Cell Size; Cell physiology; Cells; Cellular Metabolic Process; Characteristics; Chronic; Country; Data; Disease; Elderly; Environment; Epigenetic Process; Etiology; Fibroblasts; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genomics; Human; IL6 gene; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Inflammation; Inflammatory; Inflammatory Response; Lead; Life; Longevity; Metabolic; Metabolic Pathway; Metabolism; Methods; Microglia; Mitotic; Molecular; Morphology; Neuroglia; Neurons; Nucleotides; Organ; Pathway interactions; Patients; Phase; Phenotype; Physiological; Plant Roots; Predictive Factor; Process; Proteomics; Sampling; Signal Transduction; Source; System; Technology; Test Result; Testing; Tissues; Up-Regulation; Work; age related; aged; aging brain; cell type; clinically relevant; disorder control; effective therapy; experimental study; extracellular; functional decline; healthy aging; in vitro Model; induced pluripotent stem cell; inflammatory marker; insight; neutralizing antibody; novel; nucleotide metabolism; pathological aging; preservation; protein biomarkers; response; senescence; small molecule; stem cells; transcriptome sequencing; transcriptomics; transdifferentiation

Project Summary Age is the single strongest predictive factor for Alzheimer's disease (AD). The vast majority of AD cases arise sporadically in the seventh decade of life or beyond, with no known etiology aside from advanced age. To understand cellular and molecular changes at the root of AD, studies need experimental methods that discrim- inate healthy from pathological aging. Until now, options for in vitro study of aged human neurons, the cell type devastated by AD, have been lacking. This proposal will use induced neurons (iNs), a method that generates neurons from fibroblasts by direct transdifferentiation, to study the cellular processes in neuronal aging and AD. Unlike induced pluripotent stem cell (iPSC)-derived neurons, which pass through a stem cell intermediate phase and become physiologically rejuvenated, iNs retain age-related features of their source fibroblasts. Gene expression, epigenetic marks, and cell metabolism in iNs correspond to the age of the donor. Using the iN system, this proposal will evaluate the interaction between two age-correlated factors associated with the AD brain: cellular senescence and inflammation. Preliminary data demonstrate that iNs from AD patients are more likely to show protein markers of senescence and upregulation of senescence-associated genes than iNs from healthy aged controls (CTL). In Aim 1, senescent and non-senescent cells from AD and CTL Iines will be examined by RNA-Seq and ATAC-Seq. These analyses will identify pre-existing differences in non-senescent AD neurons that differentiate them from CTL as well as specific components of cellular senescence that are unique to neurons, a cell type in which the existence of senescence remains controversial. In other tissues, senescent cells release inflammatory factors (collectively termed the senescence associated secretory pheno- type or SASP) that disrupt the local environment, contributing to age-related tissue dysfunction. In Aim 2, the ability of secreted factors from AD and CTL iNs to activate human astrocytes and microglia will be assessed. These experiments will generate a list of neuronal components of the SASP and identify which are contributors to the chronic inflammation that arises with AD. Finally, Aim 3 will examine cellular processes hypothesized to be upstream of senescence. Prior work and preliminary data show that AD and CTL iNs differ in their cellular metabolism and intracellular nucleotide pools. The nucleotide content of AD and CTL iNs will be compared, and small molecules will be used to manipulate components of nucleotide synthesis or salvage and test the resulting impact on senescence. These studies will reveal whether inherent differences in nucleotide metab- olism lead to increased rates of cellular senescence and contribute to the inflammatory response. As a whole, these studies will provide novel insights into how senescence and inflammation interact within the aged neuronal environment that is permissive to AD.

项目摘要 年龄是阿尔茨海默氏病（AD）的最强预测因素。绝大多数广告案件出现 在生命的第七个十年中，零星的病因除了高级时代，没有知名的病因。到 了解AD根部的细胞和分子变化，研究需要歧视的实验方法 病理性衰老健康。到目前为止，对老年人神经元的体外研究（细胞类型）的选择 被广告破坏，缺乏。该建议将使用诱导的神经元（INS），一种生成的方法 通过直接转分化的成纤维细胞的神经元研究神经元衰老和 广告。与诱导的多能干细胞（IPSC）衍生的神经元不同，该神经元通过干细胞中间体 相位并在生理上恢复活力，INS保留其源成纤维细胞的年龄相关特征。 INS中的基因表达，表观遗传标记和细胞代谢对应于供体的年龄。使用 在系统中，该提案将评估两个与年龄相关的因素之间的相互作用 AD大脑：细胞衰老和炎症。初步数据表明，AD患者的INS是 比INS更可能显示出衰老和衰老相关基因上调的蛋白质标志物 来自健康的老年对照（CTL）。在AIM 1中，来自AD和CTL Iines的衰老和非年代细胞将是 由RNA-SEQ和ATAC-SEQ检查。这些分析将确定非浆液性的先前存在的差异 将它们与CTL以及细胞衰老的特定成分区分开的AD神经元 神经元独有的是一种细胞类型，其中衰老的存在仍然存在争议。在其他组织中， 衰老细胞释放炎症因子（共同称为衰老相关的分泌势 破坏当地环境的类型或SASP），导致与年龄相关的组织功能障碍。在AIM 2中 将评估来自AD和CTL INS激活人类星形胶质细胞和小胶质细胞的分泌因子的能力。 这些实验将生成SASP的神经元成分列表，并确定哪些是贡献者 伴有AD引起的慢性炎症。最后，AIM 3将检查假设的细胞过程 成为衰老的上游。先前的工作和初步数据表明，AD和CTL INS的细胞不同 代谢和细胞内核苷酸池。将比较AD和CTL INS的核苷酸含量， 小分子将用于操纵核苷酸合成或挽救的成分，并测试 导致对衰老的影响。这些研究将揭示核苷酸代谢的固有差异是否存在 牙齿会导致细胞衰老率提高，并导致炎症反应。总体而言 这些研究将提供有关衰老和炎症如何相互作用的新颖见解 允许AD的神经元环境。