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：
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
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/10276761
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).

项目摘要目前，约有570万美国人患有阿尔茨海默氏病（AD），代表着大量烧伤社会和我们的医疗保健系统。尽管长期知道广告涉及异常 Aβ42-Plaques和神经原纤维缠结（NFT；由高磷酸化tau组成）A的积累成功的AD治疗尚未定义。成功的疗法可能涉及广告风险患者和疾病发作前的早期干预。累积数据支持早期事件可能有助于广告发育包括活性氧（ROS）和脂质代谢的失调。这些功能似乎是断开连接的，直到我们最近发现升高神经元内的ROS会诱导过氧化脂质的形成，从而从神经元周围神经胶质。在神经胶质中，这些脂质形成LD，并且已经解决了。抑制这个过程驱动ROS诱导的神经毒性。在慢性神经元ROS期间，神经胶质与LD和死亡，使神经元脆弱。该途径在苍蝇和小鼠中保守，并具有支持性人类数据。目前，我们正在揭示Glial LD形成在AD中的潜在作用。果蝇的初步数据证明GWAS定义为AD的危险因素的基因会融合到神经胶质LD形成途径上。 ABCA转运蛋白ABCA1和ABCA7在压力神经元中需要进行神经胶质LD形成，可能是出口过氧化脂质。此外，在Glia中需要四个基因 - LRP1，PICALM，CD2AP和AP2A2 - 可能是摄取过氧化脂质的。我们还发现，在神经胶质中需要疾病基因tau。 LD形成。最后，破坏神经胶质LD形成的初步和已发布的数据支持可能会驱动细胞外Aβ42积累，NFT形成和疾病。总体而言，我们假设Glial LD形成是一个早期的事件，可减弱健康的大脑中的ROS，并且此过程变得过早在AD中有缺陷。在我们当前的数据的基础上，我们将定义Glial LD形成的潜在贡献 ROS诱导的神经变性，无法差的Aβ42堆积和NFT形成的缺陷。 AIM 1将调查广告风险基因和与AD相关的变体，用于在ROS升高期间参与神经胶质LD形成神经元使用新型的人源性蝇模型。 AIM 2将专注于Tau作为神经胶质LD的潜在介体在新颖和建立的蝇模中形成，定义了人类同工型和突变的不同影响，并评估神经胶质LD形成中的缺陷是否有助于TAU的磷酸化/聚集。最后的， AIM 3将探索哺乳动物系统中苍蝇的定义机制。最初，已建立的老鼠神经元：可以测量从胁迫神经元到神经胶质及其的脂质转移的神经培养模型积累成神经胶质LD将用于测试广告风险基因和TAU是否可以介导该过程。此外，病理研究将在验尸后组织进行，以确定LD之间的相关性存在和疾病特征（例如Aβ42-Plaques，NFT，疾病严重程度以及AD风险变体的存在）。