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

项目总结 阿尔茨海默病(AD)和其他神经官能症(如额叶痴呆、进行性核上性痴呆 瘫痪和皮质基底膜变性)，微管相关蛋白tau异常错误折叠和 堆积成不溶的淀粉样包涵体，可见为神经元内的“神经原纤维缠结”(NFTs) 在死后的脑部分析中。NFTs影响这些疾病的特定脑区，提示有选择性 某些神经细胞类型和/或神经回路对这些损害的脆弱性。耐人寻味的是， NFTS与AD患者认知症状和神经退行性变的进展密切相关， 细胞外抗体包涵体比阿尔茨海默病的另一个诊断标志物--细胞外抗体包涵体更强。积累证据 支持这样一种假设，即由tau和其他相关蛋白形成的蛋白质聚集体 神经退行性疾病[例如帕金森氏病的α-突触核蛋白，肌萎缩侧索硬化症的TDP-43， 和亨廷顿病(HD)的突变亨廷顿蛋白]在解剖连接的区域之间传播 大脑类似于传染性的普恩病毒。“类Prion”扩散导致可溶性同源物的成核聚集 下游神经元中的蛋白质，从而可能推动非细胞自主性疾病的进展。我们的长- 学期目标是阐明蛋白质聚集体扩散的细胞机制和完整的毒性。 中枢神经系统(CNS)。我们之前已经建立了一种细胞间传播的动物模型 利用功能强大的果蝇基因工具独立标记与HD相关的淀粉样聚集体 飞行中枢神经系统中神经元和神经胶质细胞的亚群。我们的初步实验表明，德雷珀，一种进化上- 保守的胶质细胞清道夫受体在神经元聚集相关的发病机制中起着核心作用。这个 该项目的总体目标是建立新的果蝇AD和紧张症模型，以确定如何 神经元-神经胶质细胞的相互作用有助于tau的毒性和体内扩散。我们的中心假设是动态的 神经元突触和吞噬胶质细胞之间的相互作用促进Pron样扩散和 在一个完整的大脑中聚集了tau。这一假设将在两个独立的具体目标中得到检验。在目标1中， 人类tau聚集体的细胞间转移将被研究在突触连接的神经元之间，非突触连接的神经元之间 突触连接的神经元，以及神经元和胶质细胞之间。胶质细胞吞噬作用在这些疾病中的作用 此外，还将探索传播模式。在目标2中，我们将测量不同人类的突触毒性效应 果蝇感觉神经元靶向群体中的tau变异。这项建议具有很高的创新性，因为它将审查 细胞自主和非细胞自主过程使用新的果蝇工具从基因上获得和 在同一个苍蝇大脑中操纵多个不同的细胞群。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以及在很大程度上被低估的作用的问题 吞噬细胞在AD和其他神经退行性疾病进展中的作用。从以下方面获得机械洞察力 这项研究将阐明针对这些致命疾病的潜在新的细胞类型特异性治疗靶点。

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.