Drosophila models for tau toxicity and spreading in the central nervous system

tau 毒性和中枢神经系统扩散的果蝇模型

• 批准号: 9902302
• 负责人: Margaret Panning Pearce
• 金额: $ 14.25万
• 依托单位: UNIVERSITY OF THE SCIENCES PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902302
• 关键词: Address; Affect; Afferent Neurons; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyotrophic Lateral Sclerosis; Anatomy; Animal Model; Appearance; Autopsy; Axon; Behavior; Brain; Brain region; Cell Culture Techniques; Cell model; Cells; Characteristics; Complex; Confocal Microscopy; Cytoplasm; Dementia; Dendrites; Disease; Disease Progression; Drosophila genus; Drosophila melanogaster; Environment; Frontotemporal Dementia; Functional disorder; Genetic; Genetic Models; Goals; Human; Huntington Disease; Huntington gene; Huntington protein; Impaired cognition; In Vitro; Individual; Interneurons; Label; Lesion; Life Cycle Stages; Light; MAPT gene; Measures; Modeling; Molecular; Mosaicism; Mutation; Nerve Degeneration; Neuraxis; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Neuropathogenesis; Neurophysiology - biologic function; Outcomes Research; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pattern; Phagocytes; Phagocytosis; Play; Population; Prions; Process; Progressive Supranuclear Palsy; Proteins; Public Health; Quality of life; Reporting; Research; Resolution; Role; Staging; Structure; Synapses; System; Target Populations; Tauopathies; Testing; Toxic effect; Transgenes; Transgenic Model; Transgenic Organisms; Variant; Work; age related neurodegeneration; alpha synuclein; brain tissue; cell type; corticobasal degeneration; diagnostic biomarker; effective therapy; experimental study; extracellular; fly; genetic risk factor; improved; in vivo; innovation; insight; mutant; neural circuit; neurofibrillary tangle formation; neurotoxicity; olfactory sensory neurons; postsynaptic neurons; prion-like; protein TDP-43; protein aggregation; scavenger receptor; spatiotemporal; tau Proteins; tau aggregation; tau expression; tau mutation; tau-1; therapeutic target; tool; transmission process

PROJECT SUMMARY In Alzheimer’s disease (AD) and other tauopathies (e.g. frontemporal dementia, progressive supranuclear palsy, and corticobasal degeneration), the microtubule-associated protein tau abnormally misfolds and accumulates into insoluble, amyloid inclusions that are visible as intra-neuronal “neurofibrillary tangles” (NFTs) in post-mortem brain analyses. NFTs affect specific brain regions in these diseases, suggesting selective vulnerability of certain neuronal cell types and/or neural circuits to these lesions. Intriguingly, appearance of NFTs strongly correlates with the progression of cognitive symptoms and neurodegeneration in AD patients, moreso than extracellular Ab inclusions, another diagnostic marker in AD brains. Accumulating evidence supports the hypothesis that protein aggregates formed by tau and other proteins associated with neurodegenerative disease [e.g. a-synuclein in Parkinson’s disease, TDP-43 in amyotrophic lateral sclerosis, and mutant huntingtin in Huntington’s disease (HD)] spread between anatomically-connected regions of the brain similarly to infectious prions. “Prion-like” spreading results in nucleated aggregation of soluble cognate proteins in downstream neurons and could thereby drive non-cell autonomous disease progression. Our long- term goal is to elucidate the cellular mechanisms for protein aggregate spreading and toxicity in the intact central nervous system (CNS). We have previously established an animal model for cell-to-cell spreading of amyloid aggregates associated with HD using powerful Drosophila genetic tools that independently label subsets of neurons and glia in the fly CNS. Our preliminary experiments suggest that Draper, an evolutionarily- conserved glial scavenger receptor, plays a central role in aggregate-related pathogenesis in neurons. The overall objective of this project is to establish new Drosophila models of AD and tauopathies to determine how neuron-glia interactions contribute to tau toxicity and spreading in vivo. Our central hypothesis is that dynamic interactions between neuronal synapses and phagocytic glia facilitate prion-like spreading and toxicity of aggregated tau in an intact brain. This hypothesis will be tested in two independent Specific Aims. In Aim 1, inter-cellular transfer of human tau aggregates will be examined between synaptically-connected neurons, non- synaptically connected neurons, and between neurons and glia. The role of glial phagocytosis in these spreading models will also be explored. In Aim 2, we will measure the synaptotoxic effects of different human tau variants in targeted populations of fly sensory neurons. This proposal is highly innovative as it will examine cell autonomous and non-cell autonomous processes using new Drosophila tools to genetically access and manipulate multiple, distinct cell populations in the same fly brain. Importantly, this research will address critical questions about how tau aggregates exert toxicity in the brain and the largely underappreciated roles of phagocytic glia in progression of AD and other neurodegenerative diseases. Mechanistic insight gained from this research will shed light on potential new cell type-specific therapeutic targets for these fatal disorders.

项目摘要 在阿尔茨海默氏病（AD）和其他tau蛋白病（例如额颞叶痴呆、进行性核上性痴呆）中， 麻痹和皮质基底节变性），微管相关蛋白tau异常错误折叠， 聚集成不溶性的淀粉样内含物，其作为神经元内的“神经纤维缠结”（NFT）可见 在死后的大脑分析中。NFT影响这些疾病的特定脑区，表明选择性 某些神经元细胞类型和/或神经回路对这些损伤的脆弱性。有趣的是， NFT与AD患者的认知症状和神经退行性变的进展密切相关， 比细胞外抗体夹杂物更重要，细胞外抗体夹杂物是AD脑中的另一个诊断标志物。越来越多的证据 支持由tau蛋白和其他与tau蛋白相关的蛋白质形成的蛋白质聚集体的假设。 神经变性疾病[例如帕金森病中的α-突触核蛋白，肌萎缩侧索硬化中的TDP-43， 和突变亨廷顿蛋白在亨廷顿病（HD））之间的解剖连接区域的传播， 大脑类似于传染性朊病毒。“朊病毒样”扩散导致可溶性同源物的有核聚集 下游神经元中的蛋白质，从而可以驱动非细胞自主疾病进展。我们长久以来- 长期目标是阐明蛋白质聚集体在完整的细胞中扩散和毒性的细胞机制， 中枢神经系统（CNS）。我们先前已经建立了一种细胞间扩散的动物模型， 使用强大的果蝇遗传工具，独立标记与HD相关的淀粉样蛋白聚集体， 果蝇中枢神经系统中神经元和神经胶质的亚群。我们的初步实验表明，德雷珀，一个进化- 保守的神经胶质清道夫受体在神经元中聚集相关的发病机制中起核心作用。的 该项目的总体目标是建立新的AD和tau蛋白病的果蝇模型，以确定如何 神经元-神经胶质相互作用导致tau毒性和体内扩散。我们的核心假设是， 神经元突触和吞噬胶质细胞之间的相互作用促进朊病毒样扩散和毒性， 在完整的大脑中聚集了tau蛋白这一假设将在两个独立的具体目标中进行检验。在目标1中， 人tau聚集体的细胞间转移将在突触连接的神经元、非突触连接的神经元和非突触连接的神经元之间进行检查。 突触连接的神经元，以及神经元和神经胶质之间。胶质细胞吞噬作用在这些 并探讨推广模式。在目标2中，我们将测量不同人类的突触毒性效应。 在果蝇感觉神经元的靶向群体中的tau变体。这项建议极具创意，因为它将研究 细胞自主和非细胞自主的过程，使用新的果蝇工具， 操纵同一苍蝇大脑中多个不同的细胞群。重要的是，这项研究将解决关键问题， 关于tau聚集体如何在大脑中发挥毒性的问题，以及 在AD和其他神经退行性疾病的进展中的吞噬细胞神经胶质。机械的洞察力来自于 这项研究将揭示这些致命疾病的潜在新细胞类型特异性治疗靶点。