Mechanisms by which ABCA7 activity influences Alzheimer's Disease

ABCA7 活性影响阿尔茨海默病的机制

• 批准号: 10525795
• 负责人: Daniel James Rader
• 金额: $ 212.11万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525795
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Affect; Alzheimer' s Disease; Alzheimer' s disease risk; American; Apolipoprotein E; Apolipoproteins; Astrocytes; Brain; Carrier Proteins; Cells; Ceramides; Cholesterol; Code; Cognition; Dementia; Development; Family member; Functional disorder; Genetic Variation; Impaired cognition; Lead; Lecithin; Lipids; Mediating; Mediator of activation protein; Membrane; Memory; Memory Loss; Microglia; Mus; Neurons; Organ; Phospholipids; Plasma; Population; Prevalence; Regulation; Research; Research Personnel; Role; Signal Transduction; Specificity; Tertiary Protein Structure; Testing; Variant; aging population; brain cell; cell type; cognitive function; daily functioning; extracellular; genome wide association study; genomic locus; induced pluripotent stem cell; lipid metabolism; lipid transport; lipidomics; member; neurotransmission; response; translocase

Alzheimer's Disease (AD) is the most common cause of dementia, affecting nearly 6 million Americans and continuing to increase in prevalence with the aging population. AD causes progressive memory loss and cognitive impairment that can eventually lead to the total inability to perform daily functions. The brain is the most cholesterol-rich and lipid-diverse organ in the body and depends on tight regulation of lipid metabolism and transport to maintain proper neural signaling transduction and cognitive function. Several large GWAS have associated the ABCA7 gene locus with AD, with variants that are predicted to have reduced function associated with increased AD risk. ABCA7 is a member of the ATP-binding cassette transporter subfamily A (ABCA), with well described functions as membrane phospholipid (PL) translocases and mediators of cholesterol and lipid efflux from cells. The most characterized ABCA family member is ABCA1, which has been extensively characterized regarding its role in cellular phosphatidylcholine (PC) and cholesterol efflux to extracellular acceptors apolipoproteins apoA1 and apoE. ABCA7 is highly homologous to ABCA1, suggesting that ABCA? mediates transport of certain lipids from inside to outside the cell in response to acceptors like apoA1 and apoE. However, the specific lipids transported by ABCA7 and the mechanisms by which it modulates AD risk have not been established. GWAS of plasma metabolites identified a significant association of the ABCA7 gene locus with certain ceramide species. Lipidomic profiling of Abca7-/- mouse brain revealed dysregulation in several lipid classes, including ceramides, which coincided with impaired cognitive functions, suggesting a functional role of these lipids in memory and cognition. While ABCA1 is also expressed in the brain, the cellular expression of ABCA1 and ABCA 7 is different, and genetic variation at ABCA1 does not carry the same risk of AD at the population level. Therefore, it is hypothesized in this proposal, that ABCA7, in contrast to ABCA1, translocates and promotes cellular efflux of specific lipid species in specific brain cell types in an AD-protective manner, and that reduced ABCA? activity leads to cellular accumulation of toxic lipid species, contributing to neural cell dysfunction and AD. To test this hypothesis, the following research aims are proposed: 1) Determine the specific lipid species affected by deletion of ABCA7 (compared with ABCA1) in three different iPSC-derived brain cells (neurons, microglia, and astrocytes), and establish the effect of ABCA 7 deletion on AD-relevant functions of iPSC­ derived brain cells; 2) Identify ABCA7 protein domains that differentiate ABCA7 from ABCA1 with regard to specificity of lipid translocase activities; 3) Characterize the functional effects of naturally­occurring ABCA7 coding variants that are significantly associated with AD.

阿尔茨海默氏病（AD）是痴呆症的最常见原因，影响了近600万美国人，并且继续增加人口老龄化的患病率。 AD会导致渐进记忆力丧失和认知障碍，有时可能导致完全无法执行日常功能。大脑是体内最富含胆固醇和脂质的器官，取决于脂质代谢和运输的严格调节，以维持适当的神经信号传导翻译和认知功能。几个大的GWA已将ABCA7基因基因座与AD相关联，预计与AD风险增加相关的功能会降低功能。 ABCA7是ATP结合盒转运蛋白亚家族A（ABCA）的成员，其功能很好地描述为膜磷脂（PL）易位，并且来自细胞的胆固醇和脂质外排的介体。最有特征的ABCA家族成员是ABCA1，它在其在细胞磷脂酰胆碱（PC）中的作用（PC）和胆固醇外排出的细胞外受体载脂蛋白ApoA1和ApoE的作用得到了广泛的特征。 ABCA7与ABCA1高度同源，表明ABCA？响应诸如APOA1和APOE等受体，介导某些脂质从内部到外部的运输。但是，ABCA7运输的特定脂质及其调节AD风险的机制尚未建立。血浆代谢产物的GWA鉴定出ABCA7基因座与某些神经酰胺物种的显着关联。 ABCA7 - / - 小鼠脑的脂质组分析显示，包括神经酰胺在内的几种脂质类别的失调，与认知功能受损相吻合，这表明这些脂质在记忆和认知中的功能作用。虽然ABCA1在大脑中也表达，但ABCA1和ABCA 7的细胞表达不同，ABCA1的遗传变异在人群水平上也不具有相同的AD风险。因此，在该提案中假设，与ABCA1相比，ABCA7以AD保护方式易位并促进特定脑细胞类型的特定脂质物种的细胞外排，而降低了ABCA？活性导致有毒脂质物质的细胞积累，导致神经细胞功能障碍和AD。为了检验这一假设，提出了以下研究目的：1）确定在三种不同IPSC衍生的脑细胞（神经元，小胶质细胞和星形胶质细胞）中受ABCA7（与ABCA1相比）影响的特定脂质物种，并确定ABCA 7缺失对ABCA 7的影响对ABCA的作用对ABCA 7的影响。 2）确定在脂质易位酶活性方面将ABCA7与ABCA1区分开的ABCA7蛋白结构域； 3）表征与AD显着相关的自然造成的ABCA7编码变体的功能效应。