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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：
10640936
负责人：
HUGO J BELLEN
金额：
$ 45.64万
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/10640936
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 Lipid Peroxidation Lipids Mammals Measures Mediating Mediator 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 Running Severity of illness Societies Stress System Testing Time Tissues Toxic effect Up-Regulation Variant Work apolipoprotein E-4 attenuation 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 neurofibrillary tangle formation neuron loss neuronal survival neuroprotection 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).

项目总结