Cell Specific Perturbations of the Proteome in Alzheimer's Disease

阿尔茨海默病中蛋白质组的细胞特异性扰动

• 批准号: 10491855
• 负责人: HOLLIS T. CLINE
• 金额: $ 131.8万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491855
• 关键词: Acids; Affect; Affinity; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; American; Amino Acids; Amyloid beta-Protein Precursor; Animal Model; Architecture; Astrocytes; Biochemical; Biotin; Brain; Brain region; Cell Death; Cell physiology; Cells; Charge; Chemistry; Chronic; Complement; Cre driver; Data; Defect; Detection; Development; Disease; Disease Progression; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Epigenetic Process; Etiology; Genes; Genetic Transcription; Genomics; Glutamates; Goals; Hippocampus (Brain); Image; Impaired cognition; Impairment; Interneurons; Knock-in; Knowledge; Label; Learning; Light; Longitudinal Studies; Mass Spectrum Analysis; Measurement; Measures; Membrane; Memory; Memory Loss; Messenger RNA; Metabolism; Methionine; Methionine-tRNA Ligase; Methods; Microglia; Molecular; Monitor; Mouse Protein; Mus; Nature; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neurons; Neurotransmitters; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Population; Post-Translational Protein Processing; Principal Investigator; Property; Protein Biosynthesis; Protein Dynamics; Proteins; Proteome; Proteomics; Recording of previous events; Research; Research Proposals; Resources; Rest; Risk Factors; Signal Transduction; Structure; Synapses; Synaptic plasticity; Testing; Transfer RNA; Translations; aging brain; amyloid peptide; baby boomer; base; bioinformatics pipeline; brain cell; cell type; chemical genetics; classical conditioning; deep sequencing; excitatory neuron; experience; extracellular; familial Alzheimer disease; frontal lobe; genetic approach; healthy aging; human old age (65+); hyperphosphorylated tau; in vivo; inhibitory neuron; insight; memory encoding; memory retrieval; mouse model; mutant; neural circuit; neuroinflammation; neuron loss; normal aging; novel; novel marker; optical imaging; optogenetics; protein degradation; protein misfolding; proteomic signature; proteostasis; relating to nervous system; tau Proteins; tool; virtual

Alzheimer’s disease (AD) is the leading cause of aging-related cognitive decline, affecting more than 5 million Americans over 65 years old, and the number of patients is expected to climb to 13 million as baby boomers age. Our ability to learn and remember declines with age due to progressive changes in synaptic connectivity and function. Synaptic abnormalities also commonly precede neuronal loss during early stages of Alzheimer’s disease (AD) and other neurodegenerative disorders. However, we are only beginning to understand the full spectrum of these abnormalities, their contributions to cognitive decline, and the underlying mechanisms. This challenge is largely attributed to the complexity of the brain and etiologies of aging and neurodegeneration. Hallmarks of advanced Alzheimer’s disease (AD) include accumulations of extracellular amyloid peptides and intracellular hyperphosphorylated tau protein as well as chronic neuroinflammation. While genes for familial AD have been identified, which shed substantial light on the etiology of the disease, the mechanisms behind sporadic onset AD still remain a mystery. While studies of transcriptional dynamics in the brain have been transformative, transcriptional dynamics do not correlate well with protein dynamics because protein synthesis, turnover and subcellular localization are more tightly regulated spatially and temporally than transcription. Studies have suggested that proteostasis declines with age, impairing cells from managing the inevitable misfolding of proteins. Our team will study protein dynamics in animal models based on bio-orthogonal non-canonical amino acid (BONCAT) protein labeling. These methods allow us to measure dynamics in protein synthesis and degradation in specific brain cell types relevant to AD. These measurements will provide new information about the disruption of normal cellular processes. The overreaching goal of our collaborative proposal is to bridge critical gaps in knowledge by leveraging the state-of-the-art methods for bio-orthogonal non-canonical amino acid tagging (BONCAT) and quantitative mass spectrometry (MS) to identify brain cell-type contributions to synaptic and neuronal decline associated with AD.

阿尔茨海默病（AD）是与年龄相关的认知能力下降的主要原因，影响了500多万65岁以上的美国人，随着婴儿潮一代的年龄增长，患者人数预计将攀升至1300万。我们的学习和记忆能力随着年龄的增长而下降，这是由于突触连接和功能的逐渐变化。在阿尔茨海默病（AD）和其他神经退行性疾病的早期阶段，突触异常也通常先于神经元损失。然而，我们才刚刚开始了解这些异常的全部范围，它们对认知能力下降的贡献以及潜在的机制。这一挑战在很大程度上归因于大脑的复杂性以及衰老和神经变性的病因。晚期阿尔茨海默病（AD）的特征包括细胞外淀粉样肽和细胞内过度磷酸化的tau蛋白的积累以及慢性神经炎症。虽然家族性AD的基因已经被鉴定，这为疾病的病因学提供了实质性的线索，但散发性AD背后的机制仍然是一个谜。虽然对大脑中转录动力学的研究具有变革性，但转录动力学与蛋白质动力学并不相关，因为蛋白质合成、周转和亚细胞定位在空间和时间上比转录受到更严格的调控。研究表明，蛋白质稳态随着年龄的增长而下降，从而损害细胞对蛋白质不可避免的错误折叠的管理。我们的团队将研究基于生物正交非规范氨基酸（BONCAT）蛋白质标记的动物模型中的蛋白质动力学。这些方法使我们能够测量与AD相关的特定脑细胞类型中蛋白质合成和降解的动态。这些测量将提供有关正常细胞过程中断的新信息。我们合作提案的过度目标是通过利用生物正交非规范氨基酸标记（BONCAT）和定量质谱（MS）的最先进方法来弥合知识的关键差距，以确定与AD相关的突触和神经元衰退的脑细胞类型贡献。