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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目总结