Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients

评估阿尔茨海默病患者衰老和恢复活力的神经元的细胞老化

基本信息

批准号：
10522910
负责人：
FRED H GAGE
金额：
$ 116.96万
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：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522910
关键词：
3-Dimensional Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Antineoplastic Agents Apolipoprotein E Astrocytes Autopsy Binding Biological Assay Biological Process Brain Buffers Cell Aging Cell Nucleus Cells Chemicals Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Coupling Cytoplasm Data Detection Disease Disease Marker Disease Progression Effectiveness Elderly Engineering Environment Epigenetic Process Etiology Fibroblasts Genetic Genomics Goals Human Incidence Individual Knowledge Lead Malignant Neoplasms Metabolic Mitotic Modeling Molecular Nerve Degeneration Nervous system structure Neuroglia Neuronal Dysfunction Neurons Nuclear Oncogenic Onset of illness Paraffin Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Protein Isoforms Proteins Proteomics Protocols documentation Pyruvate Kinase RNA Splicing Role Structure Testing Therapeutic Tissues Transgenes Transgenic Organisms Variant Warburg Effect abeta deposition age related age related neurodegeneration aged anticancer research base base editing cancer cell cellular pathology disease phenotype disorder control drug development drug discovery genome editing injured insight lipidomics metabolic abnormality assessment metabolomics multiple omics neuroinflammation neuronal metabolism novel novel strategies paracrine preservation programs senescence single-cell RNA sequencing spatial relationship targeted treatment tau Proteins transcriptome sequencing

项目摘要

SUMMARY Alzheimer’s disease (AD) affects over 50 million people worldwide. The vast majority of patients, AD develops sporadically in the absence of any known etiology other than advanced age. Despite the fact that AD has been studied for over a century, its pathogenesis is still not completely understood, and drugs that could stop or reverse the disease progression are not yet available. Similar to the age-dependent incidence of many cancers, AD onset is believed to be caused by multiple hits of environmental, genomic, and aging-related factors. To better understand the cellular and molecular interactions between human aging and AD pathogenesis, induced neurons (iNs) directly converted from AD patient fibroblasts offer unique possibilities to model and study the disease in a human age-equivalent neuronal model. The teams around Dr. Gage and Dr. Mertens have recently shown that direct conversion of human AD patient-derived fibroblasts into induced neurons (iNs) preserves signatures of cell aging and sporadic AD and allows for the detection of cellular pathologies and disease drivers. Neuronal hypo-maturity represents a fundamental AD-related cellular state in iNs, and the cancer-associated Pyruvate Kinase M2 (PKM2) splice variant emerged as a key player that compromises mature neuronal metabolism and neuronal identity. PKM2 promotes neuronal vulnerability and de-differentiation via metabolic changes in the cytoplasm, and via epigenetic processes in the nucleus, but the relative contribution of the two mechanisms remains elusive and might differ substantially between cancer cells and post-mitotic neurons. To understand PKM2 in AD, and to develop PKM-directed therapeutics, more knowledge regarding (1) the relationship between neuronal PKM2 and hallmarks of AD in the human brain, (2) the fundamental cell biological functions of PKM2 in aged human neurons, and (3) the crosstalk between PKM-compromised neurons and their glial environment is needed. This project will challenge the importance of shared pathogenic pathways between cancer and AD, and assess age-dependently compromised neurons in the context of AD. First, the team will study the relationship between cancer-related PKM2-positive neurons and AD pathology in the post-mortem human brain. Second, the mechanistic impact of PKM2 imbalance on the metabolic state and neuronal fate stability of patient-specific iNs will be assessed by transgene- and genome editing-based approaches. Third, pharmacological compounds from the cancer field as a basis for developing PKM2-targeted therapeutics for AD will be leveraged. Fourth, using a novel human iN-based three-dimensional multicellular model, the team will study neuron-astrocyte coupling in the context of metabolically challenged iNs and their metabolic crosstalk with human astrocytes. The ultimate goals of these four aims are to gain insight into the roles of the well- established cancer protein PKM2 in age-related neurodegeneration and to exploit this knowledge to develop therapeutic strategies against AD.

概括阿尔茨海默病 (AD) 影响着全球超过 5000 万人，绝大多数 AD 患者。尽管 AD 是在除高龄之外没有任何已知病因的情况下偶尔发生的。其发病机制已被研究了一个多世纪，但仍未完全了解，并且可以使用药物与许多年龄依赖性发病率类似，尚无法阻止或逆转疾病进展。癌症、AD 发病被认为是由环境、基因组和衰老相关的多重因素造成的更好地了解人类衰老与 AD 之间的细胞和分子相互作用。从 AD 患者成纤维细胞直接转化而来的诱导神经元 (iNs) 提供了独特的可能性在人类年龄相当的神经模型中建模和研究疾病。 Gage 博士和 Mertens 博士周围的团队最近表明，人类 AD 的直接转化患者来源的成纤维细胞转化为诱导神经元 (iNs) 保留了细胞衰老和散发性 AD 的特征允许检测细胞病理和疾病驱动因素。 iNs 中与 AD 相关的基本细胞状态，以及癌症相关的丙酮酸激酶 M2 (PKM2) 剪接变体成为损害成熟神经元代谢和神经元身份的关键因素。通过细胞质的代谢变化促进神经脆弱性和去分化，并通过细胞核中的表观遗传过程，但这两种机制的相对贡献仍然难以捉摸癌细胞和有丝分裂后神经元之间可能存在显着差异，以了解 AD 中的 PKM2，并了解开发 PKM 导向的治疗方法，更多关于 (1) 神经 PKM2 之间的关系的知识和AD在人脑中的标志，（2）老年人中PKM2的基本细胞生物学功能 (3) PKM 受损的神经元与其神经胶质环境之间的串扰是必需的。该项目将挑战癌症和 AD 之间共同致病途径的重要性，以及首先，研究小组将研究这种关系。第二，癌症相关的 PKM2 阳性神经元与死后人脑中的 AD 病理之间的关系。 PKM2失衡对患者特定代谢状态和神经命运稳定性的机械影响 iNs 将通过基于转基因和基因组编辑的方法进行评估。来自癌症领域的化合物作为开发 PKM2 靶向 AD 疗法的基础第四，该团队将使用一种新颖的基于人类 iN 的三维多细胞模型进行研究。代谢受到挑战的 iN 及其代谢串扰背景下的神经元-星形胶质细胞耦合这四个目标的最终目标是深入了解人类星形胶质细胞的作用。确定了癌症蛋白 PKM2 在与年龄相关的神经变性中的作用，并利用这一知识来开发 AD 的治疗策略。