Epigenetic Modulation of Amyloid Beta-resistant Synapses in Non-demented Subjects with Alzheimer's Neuropathology

患有阿尔茨海默病神经病理学的非痴呆受试者中抗淀粉样蛋白突触的表观遗传调节

• 批准号: 9396939
• 负责人: Olga Zolochevska Cain
• 金额: $ 3.21万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-21 至 2019-07-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396939
• 关键词: Achievement; Address; Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Binding; Biological Preservation; Brain; Cause of Death; Clinical; Cognitive; Data; Dementia; Development; Disease; Electrophysiology (science); Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Evaluation; Flow Cytometry; Foundations; Functional disorder; Future; Goals; Hippocampus (Brain); Impaired cognition; Impairment; In Vitro; Individual; Injectable; Knowledge; Laboratories; Learning; Lesion; Long-Term Potentiation; Maintenance; Measures; Memory Loss; MicroRNAs; Molecular Biology Techniques; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurosciences; Pathology; Patients; Pharmacology; Presynaptic Terminals; Proteins; Proteomics; Reporting; Research; Research Personnel; Resistance; Role; Slice; Symptoms; Synapses; Synaptosomes; Techniques; Testing; Tg2576; Toxic effect; Training; Western Blotting; Wild Type Mouse; Work; abeta accumulation; abeta oligomer; abeta toxicity; age related; career; cognitive ability; cognitive function; demented; density; design; effective therapy; experimental study; extracellular; hyperphosphorylated tau; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; neuropathology; non-demented; novel; prevent; response; skills; synaptic function; tau aggregation; treatment strategy

PROJECT SUMMARY/ABSTRACT Several groups, including ours, have independently reported that certain individuals, here termed Non- Demented individuals with Alzheimer’s Neuropathology (NDAN), remain cognitively intact despite the presence of typical Alzheimer’s Disease (AD) neuropathology – extracellular amyloid beta (Aβ) aggregates and hyperphosphorylated tau-containing intracellular neurofibrillary tangles (NFTs). The main goal of our research is to unveil the yet unknown mechanisms responsible for preservation of cognitive function in NDAN in order to develop novel effective therapies to treat AD, which will be centered on inducing cognitive resistance in anyone affected by AD. Synaptic dysfunction due to the disrupting binding of toxic small Aβ and tau oligomers is one of the earliest impairments in AD, believed to drive initial cognitive decline and ultimately clinical manifestation of the disease. In previous work we found that synapses of NDAN subjects are resistant to the dysfunctional binding of toxic A oligomers, a previously unappreciated phenomenon consistent with their evading clinical manifestation of AD. In order to gain a more comprehensive understanding of synaptic resistance to Aβ oligomers in NDAN individuals, we further performed proteomics of post-synaptic density (PSD) fractions of hippocampi of control (non-demented, age-matched), AD and NDAN and determined that the PSD of NDAN subjects has a unique protein signature, consistent with their unique ability to reject the toxic Aβ oligomers. Through the predictive analysis of these proteomic data, specific miRNAs were identified as potential regulators of the unique protein signature observed at NDAN PSD. In the present project, which is the next step toward achieving our main research goal, we will use ex-vivo and in-vivo models to determine whether these selected miRNAs allow synapses to acquire resistance to Aβ oligomer binding and toxicity. The extensive training I will receive while completing this project will advance my knowledge of neuroscience, and in particular Alzheimer’s Disease, my overall research skills and will help me become more intellectually mature. It will also allow me to learn additional experimental techniques, particularly electrophysiology, improving my skills and preparing me for the next step in the pursuing of a future career as an independent researcher.

项目总结/摘要 包括我们在内的几个团体独立报告说，某些人，在这里被称为非- 患有阿尔茨海默病神经病理学（NDAN）的痴呆患者，尽管存在 典型的阿尔茨海默病（AD）神经病理学-细胞外淀粉样蛋白β（Aβ）聚集体和 过度磷酸化的含tau的细胞内神经元缠结（NFT）。我们研究的主要目标 是揭示负责NDAN认知功能保护的未知机制， 开发新的有效疗法来治疗AD，这将集中在诱导任何人的认知抵抗力， 受AD影响。由于毒性小Aβ和tau寡聚体的结合破坏而导致的突触功能障碍是 AD中最早的损伤，被认为是导致最初的认知下降和最终的临床表现， 这种疾病在以前的工作中，我们发现NDAN受试者的突触对功能障碍的突触有抵抗力， 毒性A β寡聚体的结合，这是一种以前未被认识到的现象，与其逃避临床治疗一致。 AD的表现。为了更全面地了解突触对Aβ的抵抗 在NDAN个体中的低聚物，我们进一步进行了突触后密度（PSD）组分的蛋白质组学研究。 对照组（非痴呆，年龄匹配），AD和NDAN的PSD 受试者具有独特的蛋白质特征，这与其排斥毒性Aβ寡聚体的独特能力一致。 通过对这些蛋白质组数据的预测分析，特异性miRNA被鉴定为潜在的 在NDAN PSD观察到的独特蛋白质特征的调节剂。在目前的项目中，这是下一个 为了实现我们的主要研究目标，我们将使用离体和体内模型来确定是否 这些选择的miRNA允许突触获得对Aβ寡聚体结合和毒性的抗性。的 在完成这个项目的同时，我将接受广泛的培训，这将提高我对神经科学的认识， 特别是阿尔茨海默病，我的整体研究技能，将帮助我变得更加聪明， 成熟它还将使我能够学习更多的实验技术，特别是电生理学， 提高我的技能，并为我在追求未来的职业生涯作为一个独立的下一步做好准备 研究员