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

基本信息

批准号：
10473724
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
项目类别：
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/10473724
关键词：
ATP binding cassette transporter 1 Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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).

项目概要目前，约有 570 万美国人患有阿尔茨海默氏病 (AD)，这给人类带来了沉重负担尽管长期以来人们都知道 AD 涉及异常行为。 Aβ42 斑块和神经原纤维缠结（NFT；由过度磷酸化的 Tau 蛋白组成）的积累 AD 的成功治疗尚未确定。成功的治疗可能涉及识别以下疾病。 AD 风险患者和疾病发作前的早期干预支持早期事件。可能导致 AD 发病的因素包括活性氧 (ROS) 的异常上调和直到我们最近发现这些特征似乎是相互关联的。神经元内ROS的升高会诱导过氧化脂质的形成，这些脂质从神经元转移到在神经胶质细胞内，这些脂质形成 LD，并且可能被抑制。过程驱动 ROS 诱导的神经毒性。在慢性神经元 ROS 过程中，神经胶质细胞因 LD 和死亡，使神经元变得脆弱，这条通路在果蝇和小鼠中是保守的，人类数据也有支持。目前，我们正在揭示果蝇中胶质细胞 LD 形成的潜在作用。证明被 GWAS 定义为 AD 危险因素的基因汇聚到神经胶质 LD 形成途径上。 ABCA 转运蛋白 ABCA1 和 ABCA7 是应激神经元中神经胶质细胞 LD 形成所必需的，可能是此外，神经胶质细胞需要四个基因——LRP1、PICALM、CD2AP 和 AP2A2。我们还发现，神经胶质细胞内需要疾病基因 Tau。最后，初步和已发表的数据支持破坏神经胶质 LD 的形成可能会驱动细胞外 Aβ42 积累、NFT 形成和疾病。总体而言，我们认为神经胶质 LD 形成。是一个早期事件，会减弱健康大脑中升高的 ROS，并且这个过程变得过早根据我们当前的数据，我们将定义胶质细胞 LD 形成的潜在贡献。将研究 ROS 诱导的神经变性、不溶性 Aβ42 积聚和 NFT 形成的缺陷。 AD风险基因和AD相关变异参与ROS升高期间神经胶质LD的形成使用新型人源化果蝇模型的神经元将重点关注 Tau 作为神经胶质 LD 的潜在调节剂。新颖和已建立的果蝇模型中的形成，定义人类 Tau 亚型和突变的不同影响，并评估胶质细胞 LD 形成的缺陷是否会导致 Tau 最后的磷酸化/聚集。目标 3 将探索哺乳动物系统中果蝇的明确机制。神经元：神经胶质细胞共培养模型，可以测量从应激神经元到神经胶质细胞的脂质转移及其神经胶质 LD 的积累将用于测试 AD 风险基因和 Tau 是否可以介导这一过程。将对死后 AD 组织进行病理学研究，以确定 LD 之间的相关性存在和疾病特征（例如 Aβ42 斑块、NFT、疾病严重程度和 AD 风险变异的存在）。