AMYLOIDOGENIC INDUCTION OF CELLULAR SENESCENCE IN ALZHEIMER'S DISEASE

阿尔茨海默病中细胞衰老的淀粉样诱导

• 批准号: 10672372
• 负责人: ANDREW D. MIRANKER
• 金额: $ 41.49万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672372
• 关键词: ATAC-seq; Adipocytes; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Astrocytes; Automobile Driving; Autopsy; Behavior; Binding; Biological Assay; Biological Markers; Biology; Biophysics; Brain; Brain region; Cell Aging; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Central Nervous System; Characteristics; Chemicals; Coupled; DNA Methylation; Data; Development; Disease; Disparate; Endothelial Cells; Environment; Epigenetic Process; Exhibits; Experimental Models; Exposure to; Fatty Acids; Fibroblasts; Genetic; Genetic Transcription; Genomic Instability; Grant; Human; Hydrogen Peroxide; In Vitro; Inflammatory; Ionizing radiation; Link; Lipids; Machine Learning; Measurement; Measures; Membrane Proteins; Mesenchymal Stem Cells; Microglia; Modeling; Molecular; Molecular Profiling; Nerve Degeneration; Neuroglia; Neurologic; Oncogene Activation; Organism; Pathogenesis; Pathologic; Pathway Analysis; Patients; Peripheral; Phenotype; Physiological; Play; Radiation; Regional Disease; Role; Sampling; Severity of illness; Signal Transduction; Slice; Solubility; Techniques; Testing; Therapeutic; Tissues; Validation; abeta oligomer; age related; biological systems; biomarker development; biophysical techniques; brain cell; cell type; experimental study; gene network; human tissue; in vivo; irradiation; molecular modeling; molecular phenotype; nervous system disorder; neuroinflammation; neuropathology; novel; novel marker; oligodendrocyte progenitor; reconstitution; response; senescence; simulation; single-cell RNA sequencing; stem cells; stressor; tau Proteins; telomere; therapeutic target

PROJECT SUMMARY Cellular senescence, one of the major hallmarks of aging, describes the sudden inability for cells to divide. Senescent cells often accumulate with age, in response to physical and chemical stressors (genomic instability, telomere attrition, irradiation, etc.), though the overlap between these stressors and neurological diseases such as Alzheimer’s Disease (AD) is currently unknown. In-vitro experiments of senescence often utilize contrived stressors such as hydrogen peroxide or radiation, that may not be physiologically relevant for age-related diseases such as AD. Furthermore, the senescence phenotypes observed in vitro are likely not complete models for what is occurring in dynamic biological systems. Soluble amyloid-beta oligomers (Aβo), an important hallmark in AD, have been shown to potently induce senescence in a variety of brain cell types and environments, in contrast to fibrillar Ab. Aβo is thought to bind membrane proteins and subsequently signal downstream aggregation of related amyloids such as tau. In fact, the presence of endogenous Aβo is one of the strongest indicators of disease severity in AD models and organisms, suggesting a link between AD and cellular senescence that is only beginning to be explored. In order to study this association, we propose to combine gold-standard techniques and single-cell omics data in order to define heterogenous genetic and epigenetic signatures of senescence that are distinctly a function of their induction type. Doing so will also produce robust signatures and biomarkers of senescence in brain cells that can be utilized for the pathological phenotyping of human tissues. These measures will also allow for the comparison of disparate senescent behaviors to help identify lab-derived amyloids that best resemble patient-derived constructs. We will evaluate multiple lab-derived Aβo constructs, including those stabilized from lipids located in predominantly diseased regions of the brain. Observations would be synergistically coupled with solution biophysics experiments and molecular modeling, providing analogous structural data for each inducer type. Taken together, these measurements will uniquely profile senescence in brain cells, define the degree of overlap between endogenous senescence inducers and those reconstituted in the lab, and highlighting how AD risk is modulated by cellular senescence.

项目概要 细胞衰老是衰老的主要标志之一，描述的是细胞突然无法分裂。 衰老细胞通常会随着年龄的增长而积累，以应对物理和化学应激源（基因组不稳定、 端粒磨损、辐射等），尽管这些压力源与神经系统疾病（例如 由于阿尔茨海默病（AD）目前尚不清楚。衰老的体外实验经常利用人为的方法 压力源，例如过氧化氢或辐射，可能与年龄相关的生理学无关 AD等疾病。此外，体外观察到的衰老表型可能不是完整的模型 动态生物系统中正在发生的事情。 可溶性β-淀粉样蛋白寡聚体 (Aβo) 是 AD 的一个重要标志，已被证明可以有效诱导 与纤维状抗体相比，多种脑细胞类型和环境中的衰老。 Aβo 被认为可以结合 膜蛋白，随后向相关淀粉样蛋白（如 tau）的下游聚集发出信号。实际上， 内源性 Aβo 的存在是 AD 模型中疾病严重程度的最强指标之一 生物体，表明 AD 和细胞衰老之间的联系才刚刚开始被探索。 为了研究这种关联，我们建议将黄金标准技术和单细胞组学结合起来 数据来定义衰老的异质遗传和表观遗传特征，这些特征明显是 它们的感应类型的功能。这样做还将产生强大的衰老特征和生物标志物 可用于人体组织病理表型分析的脑细胞。这些措施也将允许 用于比较不同的衰老行为，以帮助识别与实验室衍生的最相似的淀粉样蛋白 源自患者的构建体。我们将评估多种实验室衍生的 Aβo 构建体，包括那些稳定化的 Aβo 构建体 脂质位于大脑主要患病区域。观察结果将与 溶液生物物理实验和分子建模，为每个诱导物提供类似的结构数据 类型。总而言之，这些测量结果将独特地描述脑细胞的衰老情况，定义衰老的程度 内源性衰老诱导剂与实验室重建的诱导剂之间的重叠，并强调 AD 如何 风险是由细胞衰老调节的。

项目成果

Defining the Neuropathological Aggresome across in Silico, in Vitro, and ex Vivo Experiments.

• DOI: 10.1021/acs.jpcb.0c09193
• 发表时间: 2021-03-04
• 期刊: The journal of physical chemistry. B
• 作者: Gomes GN;Levine ZA
• 通讯作者: Levine ZA

Tick tock, tick tock: Mouse culture and tissue aging captured by an epigenetic clock.

• DOI: 10.1111/acel.13553
• 发表时间: 2022-03
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Minteer C;Morselli M;Meer M;Cao J;Higgins-Chen A;Lang SM;Pellegrini M;Yan Q;Levine ME
• 通讯作者: Levine ME