IMPACTS OF GLIAL LIPID DROPLETS ON OXIDATIVE STRESS AND NEURODEGENERATION IN ALZHEIMER'S DISEASE

胶质脂滴对阿尔茨海默病氧化应激和神经变性的影响

• 批准号: 10276761
• 负责人: HUGO J BELLEN
• 金额: $ 47.57万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10276761
• 关键词: ATP binding cassette transporter 1; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; American; Amyloid beta-42; Apolipoprotein E; Apolipoproteins; Attenuated; Autopsy; Brain; Cells; Chronic; Coculture Techniques; Data; Defect; Development; Disease; Disease Progression; Drosophila genus; Early Intervention; Endocytosis; Event; Future; Genes; Glutamates; Healthcare Systems; Human; Immunohistochemistry; Investigation; Knowledge; Lentivirus; Link; Lipids; Mammals; Measures; Mediating; Mediator of activation protein; Microglia; Modeling; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Onset of illness; Orthologous Gene; Oxidative Stress; Pathologic; Pathway interactions; Patients; Phosphorylation; Play; Process; Production; Protein Isoforms; Publishing; RNA Interference; Rattus; Reactive Oxygen Species; Research; Resolution; Role; Severity of illness; Societies; Stress; System; Testing; Time; Tissues; Toxic effect; Up-Regulation; Variant; Work; attenuation; base; cerebral atrophy; disorder risk; extracellular; fly; genetic risk factor; genome wide association study; human data; hyperphosphorylated tau; insight; interdisciplinary approach; lipid mediator; lipid metabolism; loss of function; neuron loss; neurotoxicity; new therapeutic target; novel; premature; response; risk variant; small hairpin RNA; tau Proteins; tau aggregation; therapeutic target; uptake

PROJECT SUMMARY Currently, ~5.7 million Americans live with Alzheimer’s disease (AD), representing a significant burden on society and our healthcare system. Despite long-standing knowledge that AD involves the aberrant accumulation of Aβ42-plaques and neurofibrillary tangles (NFT; composed of hyperphosphorylated Tau) a successful treatment for AD has yet to be defined. Successful therapies will likely involve the identification of AD-risk patients and early intervention prior to disease onset. Accumulating data support that early events that may contribute to AD-onset include the abnormal upregulation of reactive oxygen species (ROS) and dysregulation of lipid metabolism. These features were seemingly disconnected until we recently discovered that elevating ROS within neurons induces the formation of peroxidated lipids, which are transferred from the neurons to surrounding glia. Within glia, these lipids form LD and are, presumably, resolved. Inhibiting this process drives ROS-induced neurotoxicity. During chronic neuronal ROS, glia become overrun with LD and die, leaving the neurons vulnerable. This pathway is conserved in flies and mice, with supportive human data. Currently, we are uncovering the potential role of glial LD formation in AD. Preliminary data in Drosophila demonstrate that genes defined as risk factors for AD by GWAS converge onto the glial LD formation pathway. ABCA transporters, ABCA1 and ABCA7, are required in stressed neurons for glial LD formation, likely for the export of peroxidated lipids. Further, four genes – LRP1, PICALM, CD2AP, and AP2A2 – are required in glia, likely for the uptake of peroxidated lipids. We also found that the disease gene, Tau, is required within glia for LD formation. Last, preliminary and published data support that disrupting glial LD formation may drive extracellular Aβ42 accumulation, NFT formation, and disease. Overall, we hypothesize that glial LD formation is an early event that attenuates elevated ROS in healthy brains and this process becomes prematurely defective in AD. Building upon our current data, we will define potential contributions of glial LD formation defects on ROS-induced neurodegeneration, insoluble Aβ42 buildup, and NFT formation. Aim 1 will investigate AD-risk genes and AD-associated variants for involvement in glial LD formation during elevated ROS in neurons using novel humanized fly models. Aim 2 will focus on Tau as a potential mediator of glial LD formation in novel and established fly models, defining differing impacts of human Tau isoforms and mutations, and assessing if defects in glial LD formation can contribute to the phosphorylation/ aggregation of Tau. Last, Aim 3 will explore defined mechanisms from flies in mammalian systems. Initially, an established rat neuron:glia co-culture model that can measure lipid transfer from stressed neurons to glia and their accumulation into glial LD will be used to test if AD-risk genes and Tau can mediate this process. Further, pathological studies will be performed on post-mortem AD tissue to determine correlations between LD presence and disease features (e.g. Aβ42-plaques, NFT, disease severity, and presence of AD-risk variants).

项目总结 目前，约有570万美国人患有阿尔茨海默病(AD)，这对 社会和我们的医疗体系。尽管人们早就知道阿尔茨海默病与 Aβ42-斑块和神经原纤维缠结(NFT；由过度磷酸化的Tau组成)的积聚 阿尔茨海默病的成功治疗尚未确定。成功的治疗很可能涉及到识别 高危患者和发病前的早期干预。越来越多的数据支持早期事件 可能与AD发病有关的因素包括活性氧自由基(ROS)异常上调和 脂代谢失调。在我们最近发现这些特征之前，这些特征似乎是不相关的 神经元内ROS升高会导致过氧化脂质的形成，而过氧化脂质是从 神经元连接到周围的神经胶质细胞。在胶质细胞内，这些脂类形成LD，并可能被分解。抑制这一点 过程驱动ROS诱导的神经毒性。在慢性神经元ROS过程中，胶质细胞被LD和 死亡，使神经元变得脆弱。这条途径在苍蝇和老鼠身上是保守的，有支持人类的数据。 目前，我们正在揭示胶质细胞LD形成在AD中的潜在作用。果蝇的初步数据 研究表明，被Gwas定义为阿尔茨海默病危险因素的基因汇聚到胶质细胞LD的形成途径上。 ABCA转运体ABCA1和ABCA7是应激神经元形成胶质细胞LD所必需的，可能是 过氧化脂质的出口。此外，胶质细胞还需要四个基因--LRP1、PICALM、CD2AP和AP2A2， 很可能是过氧化脂质的摄取。我们还发现，疾病基因tau在神经胶质细胞中是必需的 LD队形。最后，初步和已发表的数据支持，扰乱胶质细胞LD的形成可能会推动 细胞外Aβ42积聚、NFT形成和疾病。总体而言，我们假设胶质细胞LD的形成 是一种早期事件，可减弱健康大脑中升高的ROS，并且这一过程变得过早 在AD中有缺陷。基于我们目前的数据，我们将确定胶质细胞LD形成的潜在贡献 ROS诱导的神经退行性变、不溶性Aβ42积聚和NFT形成的缺陷。AIM 1将调查 AD危险基因和AD相关变异体参与脑内ROS升高时胶质细胞LD的形成 使用新的人源化苍蝇模型的神经元。Aim 2将重点关注Tau作为神经胶质细胞LD的潜在介体 在新的和已建立的苍蝇模型中形成，定义了人类Tau亚型和突变的不同影响， 以及评估胶质细胞LD形成的缺陷是否有助于Tau的磷酸化/聚集。最后的, 目标3将探索哺乳动物系统中苍蝇的明确机制。最初，已建立的老鼠 神经元：神经胶质细胞共培养模型，可以测量应激状态下神经元到神经胶质细胞的脂质转移及其 神经胶质细胞LD的积聚将被用来测试AD风险基因和Tau是否可以调节这一过程。此外， 将对死后AD组织进行病理学研究，以确定LD与 存在和疾病特征(例如，Aβ42-斑块、NFT、疾病严重程度和AD风险变异的存在)。