Specificity of ABCA7-mediated lipid efflux and its effects on intracellular lipid metabolism in neural cells

ABCA7介导的脂质流出的特异性及其对神经细胞细胞内脂质代谢的影响

• 批准号: 10591201
• 负责人: Nicholas Lyssenko
• 金额: $ 22.32万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591201
• 关键词: ATP-binding cassette transport; Affect; African ancestry; Age; Age Years; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Architecture; Astrocytes; Biochemical; Brain; Cell membrane; Cells; Cessation of life; Cholesterol; Cholesterol Homeostasis; Chromosome 21; Data; Dementia; Dimensions; Disease; Down Syndrome; Early Onset Familial Alzheimer' s Disease; Electrospray Ionization; Engineering; Etiology; European ancestry; Exhibits; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Glioblastoma; Healthcare Systems; High Density Lipoproteins; Hippocampus; Human; Individual; Induced pluripotent stem cell derived neurons; Investigation; Knowledge; Label; Late Onset Alzheimer Disease; Lecithin; Link; Lipids; Longevity; Mass Spectrum Analysis; Measures; Mediating; Mediator; Metabolic; Microglia; Nerve Degeneration; Neuroblastoma; Neurons; Parietal Lobe; Pathogenesis; Pathologic; Pathology; Performance; Phospholipids; Phosphotransferases; Physiology; Population; Productivity; Proteins; Publishing; Radioactive; Research Personnel; Risk; Role; Shotguns; Specificity; Testing; Thin Layer Chromatography; Tissues; Trisomy; Variant; comparative; extracellular; gene function; genome wide association study; high density lipoprotein-1; lipid metabolism; lipidomics; loss of function; loss of function mutation; member; mouse model; neural; neuron loss; particle; preference; tau Proteins

Project Summary/Abstract Alzheimer's disease (AD) dementia has emerged as a major burden on the healthcare system and a major barrier to human longevity, especially productive human longevity. Genetics of familial early-onset AD, pathological changes in the brain of sporadic late-onset AD patients and pathological changes in the brain of individuals with Down syndrome, who frequently have increased expression of amyloid precursor protein (APP) owing to partial trisomy of chromosome 21, all point to APP and its cleavage product amyloid β (Aβ) peptide as major causative factors in AD pathogenesis. However, other factors may also play a role. The genome-wide association studies (GWAS) of the architecture of common genetic predisposition to AD, genetic investigations of rare loss-function mutations and studies in mouse models of AD have implicated ATP-binding cassette transport subfamily A member 7 (ABCA7) in AD pathogenesis. A closely related protein, ATP-binding cassette transport subfamily A member 1 (ABCA1) has been implicated in AD in the GWAS and animal studies. In our preliminary data, we show that individuals with low ABCA7 protein levels have a greater risk for developing AD pathology. Both ABCA1 and ABCA7 mediate formation of high-density lipoprotein (HDL) particles from cell lipids. In preliminary data, we show that ABCA7- and ABCA1-HDL significantly differ in the lipid composition. Recently, we published the altered lipidostasis hypothesis that draws on the paradigms provided by ABCA1 and another ABC A transporter, ABCA4, and poses the existence of a neurodegenerative lipid that continuously arises during normal physiology and promotes AD pathogenesis when it is not eliminated from neural cells by ABCA7. ABCA1 and ABCA4 eliminate from specific cells deleterious lipids that these cells accumulate during normal function. The purpose of the present exploratory project is to conduct comparative ABCA7 vs ABCA1 studies in specificity of lipid efflux in neural cells and to test the prediction of the lipidostasis hypothesis of AD that in the neural tissue ABCA7 mediates efflux of a specific lipid species (i.e., the neurodegenerative lipid) that is not effluxed significantly by ABCA1. To test this prediction, we will use metabolic radioactive labeling of lipids/high performance thin layer chromatography (HPTLC) and multidimensional electrospray ionization `shotgun' mass spectrometry lipidomics to compare ABCA7- and ABCA1-mediated lipid efflux/HDL and the effects that this efflux/HDL formation has on the lipid composition of the plasma membrane and whole cell in microglia C20, astrocyte glioblastoma A172 and neuroblastoma SK-N- SH cells inducibly expressing ABCA7 or ABCA1.

项目摘要/摘要 阿尔茨海默氏病（AD）痴呆症已成为医疗系统的主要伯恩（Burnen） 人类寿命的障碍，尤其是生产力的人类寿命。家庭早发广告的遗传学， 零星发作的AD患者大脑的病理变化以及大脑的病理变化 患有唐氏综合症的个体，他们经常增加淀粉样前体蛋白（APP）的表达 由于染色体21的部分三体三体，全部指向APP及其裂解产物淀粉样β（Aβ）胡椒 AD发病机理中主要基因组的主要因素。但是，其他因素也可能发挥作用。 对AD的常见遗传易感性结构，遗传研究的结构（GWAS） AD小鼠模型中罕见的损耗功能突变和研究已实现ATP结合盒 在AD发病机理中转运亚家族7（ABCA7）。紧密相关的蛋白质，ATP结合盒 在GWAS和动物研究中，在AD中隐含了转运亚家族1（ABCA1）。在我们的 初步数据，我们表明，ABCA7蛋白水平较低的个体具有更大的开发AD风险 病理。 ABCA1和ABCA7介导了细胞的高密度脂蛋白（HDL）颗粒的形成 脂质。在初步数据中，我们表明脂质组成中的ABCA7-和ABCA1-HDL显着差异。 最近，我们发表了改变的Lipidostasis假设，该假设借鉴了ABCA1提供的范例 另一个ABC是转运蛋白ABCA4，并构成了神经退行性脂质的存在 在正常生理过程中连续出现，并在没有从中消除AD发病机理 ABCA7神经细胞。 ABCA1和ABCA4从这些细胞的特定细胞有害脂质中消除 在正常功能期间积聚。本探索项目的目的是进行比较 ABCA7与ABCA1在神经细胞中脂质外排的特异性研究并测试脂肪替代的预测 AD的假设是，在神经组织中，ABCA7介导了特定脂质物种的外排（即 神经退行性脂质）未被ABCA1显着排出。为了测试这一预测，我们将使用 脂质/高性能薄层色谱（HPTLC）的代谢放射性标记和 多维电喷雾 电离 “ shot弹枪”质谱脂肪组学以比较ABCA7-和 ABCA1介导的脂质外排/HDL以及该外排/HDL形成对脂质组成的影响 小胶质细胞C20中的质膜和全细胞 SH细胞表达ABCA7或ABCA1。