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.

项目总结/摘要 阿尔茨海默氏病（AD）痴呆已经成为医疗保健系统的主要负担，并且是老年人的主要疾病。 人类长寿的障碍，特别是生产性人类长寿。家族性早发性AD的遗传学， 散发性迟发性AD患者脑中的病理变化和 患有唐氏综合征的个体，他们经常增加淀粉样前体蛋白（APP）的表达 由于21号染色体的部分三体性，所有人都认为APP及其裂解产物淀粉样β（Aβ）肽是 AD发病机制中的主要致病因素。然而，其他因素也可能发挥作用。全基因组 AD常见遗传易感性结构的关联研究（GWAS），遗传调查 罕见的功能缺失突变和AD小鼠模型的研究表明ATP结合盒 转运亚家族A成员7（ABCA 7）在AD发病机制中的作用。一种密切相关的蛋白质，ATP结合盒 在GWAS和动物研究中，转运亚家族A成员1（ABCA 1）与AD有关。在我们 初步数据显示，ABCA 7蛋白水平低的个体患AD的风险更大 病理ABCA 1和ABCA 7均介导细胞内高密度脂蛋白（HDL）颗粒的形成 脂质。在初步数据中，我们表明ABCA 7-和ABCA 1-HDL在脂质组成方面存在显着差异。 最近，我们发表了基于ABCA提供的范例的改变的细胞停滞假说1 和另一种ABC A转运蛋白ABCA 4，并提出了一种神经退行性脂质的存在， 在正常生理过程中持续出现，当它没有从AD中消除时， 神经细胞ABCA 7。ABCA 1和ABCA 4从特定细胞中消除有害脂质，这些细胞 在正常运行过程中积累。本探索性项目的目的是进行比较 ABCA 7与ABCA 1在神经细胞中脂质流出的特异性研究，并测试对脂质流出的预测 AD在神经组织中ABCA 7介导特定脂质种类的流出的假说（即，的 神经变性脂质），其不被ABCA 1显著流出。为了验证这一预测，我们将使用 脂质的代谢放射性标记/高效薄层色谱法（HPTLC）和 多维电喷雾 电离 “鸟枪”质谱脂质组学比较ABCA 7-和 ABCA 1介导的脂质流出/HDL以及这种流出/HDL形成对 小胶质细胞C20、星形胶质细胞胶质母细胞瘤A172和神经母细胞瘤SK-N- 诱导表达ABCA 7或ABCA 1的SH细胞。