Alterations in neuronal metabolic pathways contribute to human cognitive aging and are exacerbated in Alzheimer's disease

神经元代谢途径的改变导致人类认知衰老，并在阿尔茨海默病中加剧

• 批准号: 10740778
• 负责人: Jeffrey Ray Jones
• 金额: $ 12.42万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740778
• 关键词: ATAC-seq; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Analytical Chemistry; Bioenergetics; Biological; Biological Aging; Biological Assay; Biological Models; Brain; CDC2 gene; Carbon; Cell Cycle; Cells; ChIP-seq; Chromosomal Instability; Cognitive; Cognitive aging; DNA; DNA Damage; DNA Repair; DNA Structure; DNA biosynthesis; Data; Data Set; Dementia; Deoxyribonucleotides; Development; Disease; Down-Regulation; Elderly; Ensure; Epigenetic Process; Event; Fibroblasts; Functional disorder; Future; G1 Phase; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Transcription; Genome; Homeostasis; Human; Impaired cognition; In Vitro; Individual; Knowledge; Life; Longevity; Maps; Mediating; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Methods; Mitochondria; Mitochondrial DNA; Mitosis; Modeling; Neurons; Nuclear; Nucleotides; Pathogenesis; Pathologic; Pathway interactions; Pharmaceutical Preparations; Population; Post-Translational Protein Processing; Process; Production; Proteins; Publishing; RNA; RRM1 gene; Regulation; Rejuvenation; Repression; Reproducibility; Research; Resolution; Ribonucleotides; Role; Scientific Advances and Accomplishments; Signal Pathway; Signal Transduction; System; Techniques; Technology; Testing; Therapeutic; Thinking; Time; Transcriptional Regulation; Up-Regulation; age related; aged; cdc Genes; clinically relevant; cohort; defined contribution; differential expression; effective therapy; epigenome; experience; human disease; human old age (65+); in vivo; induced pluripotent stem cell; innovation; insight; metabolomics; methyl group; mitochondrial genome; multi-electrode arrays; new technology; non-genetic; normal aging; nucleotide metabolism; pathological aging; phosphoproteomics; postmitotic; repaired; single cell analysis; therapeutic target; tool

PROJECT SUMMARY To find therapies for altering the course of age-related diseases, experimental methods that discriminate between normal and pathological aging processes are needed. Nowhere is this need more urgent than in the quest for effective treatments for Alzheimer’s disease (AD). Despite decades of research, AD remains a debilitating, progressive, and ultimately fatal dementia with few and ineffective disease-modifying treatment options. The vast majority of cases (~95%) are sporadic, with no known cause aside from advanced age. As the population over age 65 grows, the burden of AD is destined to grow in lockstep. Avoiding this fate requires rethinking why existing efforts have been ineffective. Although AD is a disease of aged human brains, many AD studies fail to parse aging from disease. We have developed a system that lets us model aspects of human age in vitro: induced neurons (iNs). Once matured, neurons of the brain never again replicate their genome or divide. As such, post-mitotic neurons downregulate cell-cycle mediated metabolic pathways used for the synthesis of DNA building blocks, deoxyribonucleotides (dNTs) and become reliant on the salvage of ribonucleotides (rNTs). I asked if these fundamentally important homeostatic processes are maintained over the human lifespan or in AD. Multiple experimental approaches on iNs derived from 13 sporadic AD (sAD) patients against 13 cognitively normal, age-match individuals (CN), revealed dramatic differences in NT pools, with a significant increase in rNTs in CNs relative to young healthy iNs. This effect was even further exacerbated in AD iNs. I ask here if the dramatic increases in rNTs result in increased ribo-substitution in nuclear and mitochondrial DNA, thus promoting increased DNA damage and bioenergetic dysfunction in age and AD. Further, I observed significant differential expression of key cell cycle and metabolic genes such as CDK1 and RRM1, which I have confirmed at the protein level. Our proposal, for the first time, incorporates long noted pathological observations of chromosomal instability and presence of cell-cycle markers in AD into a testable model system that provides a mechanistic basis for the development of sporadic AD. In addition to the critical scientific advances this proposal aims to achieve, I will also contribute new powerful new tools and datasets to the fields of aging and AD. I have adapted our recently developed repair-seq technology to quantify ribo-substitution in aged and AD iNs. I will further map epigenetic drift over the human lifespan in neurons and quantify the neuronal capacity to generate new methyl groups for non-genetic regulation of transcription.

项目总结 寻找改变年龄相关疾病病程的治疗方法，实验方法歧视 在正常和病理性衰老过程之间是必要的。这一需求在任何地方都比 寻求治疗阿尔茨海默病(AD)的有效方法。尽管经过了几十年的研究，AD仍然是一个 衰弱的、进行性的、最终致命的痴呆症，几乎没有有效的疾病修正治疗 选择。绝大多数病例(~95%)是散发性的，除了高龄外没有已知的原因。AS 随着65岁以上人口的增长，AD的负担注定会同步增长。避免这种命运需要 重新思考为什么现有的努力没有效果。 虽然阿尔茨海默病是人类大脑老化的一种疾病，但许多关于阿尔茨海默病的研究未能将衰老与疾病分开。我们有 开发了一种系统，可以让我们在体外模拟人类年龄的各个方面：诱导神经元(INS)。一旦成熟， 大脑的神经元再也不会复制它们的基因组或分裂了。因此，有丝分裂后神经元下调 细胞周期介导的代谢途径用于DNA构建块--脱氧核糖核苷酸的合成 (DNTs)，并依赖于回收的核糖核苷酸(Rnts)。我问这些是否从根本上说很重要 动态平衡过程在人的一生中或在AD期间保持。多种实验方法 来自13名散发性AD(SAD)患者和13名认知正常、年龄匹配的个人(CN)的INS， 在NT池中显示出显著的差异，CNS中的RNT相对于年轻健康的人显著增加 移民局。这种影响在AD INS中甚至进一步加剧。我在这里问，RNTS的急剧增加是否会导致 核和线粒体DNA中的核糖核酸基取代增加，从而促进DNA损伤和 年龄和阿尔茨海默病患者的生物能量功能障碍。此外，我观察到关键细胞周期的显著差异表达 以及代谢基因，如CDK1和RRM1，我已经在蛋白质水平上证实了这一点。我们的建议， 第一次，结合了长期以来注意到的染色体不稳定和存在的 将AD细胞周期标记物转化为可检测模型系统，为AD的发展提供机制基础 零星的AD。 除了这项提议旨在实现的关键科学进步外，我还将贡献新的强大的 老龄化和AD领域的新工具和数据集。我改装了我们最近开发的Repair-Seq 对老年性和阿尔茨海默病患者的核糖体替代进行量化的技术。我将进一步绘制人类的表观遗传漂移图 神经元的寿命，并量化神经元为非遗传性基因产生新甲基的能力 转录调控。