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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

项目摘要

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.

项目概要为了找到改变与年龄相关的疾病进程的疗法，区分性的实验方法在正常和病理性衰老过程之间进行区分是最迫切的。尽管经过数十年的研究，AD 仍然是一种治疗方法。使人衰弱的、进行性的、最终致命的痴呆症，疾病缓解治疗很少且无效绝大多数病例（~95%）是散发性的，除了高龄之外没有已知的原因。随着 65 岁以上人口的增长，AD 的负担注定会同步增长。重新思考为什么现有的努力无效。尽管AD是一种老年人类大脑疾病，但许多AD研究未能将衰老与疾病分开。开发了一个系统，可以让我们在体外模拟人类年龄的各个方面：诱导神经元（iN）一旦成熟，大脑的神经元不再复制其基因组或分裂，因此，有丝分裂后的神经元下调。用于合成 DNA 构件、脱氧核糖核苷酸的细胞周期介导的代谢途径（dNT）并变得依赖核糖核苷酸（rNT）的挽救，我问这些是否从根本上重要。在人类的整个生命周期或 AD 中都维持稳态过程。 iN 源自 13 名散发性 AD (SAD) 患者与 13 名认知正常、年龄匹配的个体 (CN)，揭示了 NT 池的显着差异，CN 中的 rNT 相对于年轻健康人显着增加 iNs 中这种效应甚至进一步加剧，我在这里询问 rNT 的急剧增加是否会导致这种情况。核和线粒体 DNA 中核糖取代的增加，从而促进 DNA 损伤的增加此外，我观察到关键细胞周期的显着差异表达。以及代谢基因，例如CDK1和RRM1，我已经在蛋白质水平上证实了我们的建议。第一次，结合了长期关注的染色体不稳定性和存在的病理学观察 AD 中的细胞周期标记物转化为可测试的模型系统，为开发提供了机制基础零星的AD。除了该提案旨在实现的关键科学进步之外，我还将贡献新的强大的我已经将我们最近开发的修复序列应用于衰老和 AD 领域的新工具和数据集。我将进一步绘制人类表观遗传漂变图谱。神经元的寿命并量化神经元产生非遗传性新甲基的能力转录调控。