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.

阿尔茨海默病 (AD) 是痴呆症的最常见原因，影响着近 600 万美国人，并且随着人口老龄化，AD 患病率持续增加，导致进行性记忆丧失和认知障碍，最终导致完全无法执行日常功能。大脑是体内胆固醇最丰富、脂质最多样化的器官，依赖于脂质代谢和运输的严格调节来维持适当的神经信号转导和认知功能，几个大型 GWAS 已将 ABCA7 基因位点与 AD 及其变异联系起来。预计会减少ABCA7 是 ATP 结合盒转运蛋白亚家族 A (ABCA) 的成员，其功能已被充分描述为膜磷脂 (PL) 转位酶以及细胞中胆固醇和脂质流出的介质。成员是 ABCA1，其在细胞磷脂酰胆碱 (PC) 和胆固醇流出至细胞外受体载脂蛋白 apoA1 中的作用已被表征，并且主要apoE 与 ABCA1 高度同源，表明 ABCA? 响应 apoA1 和 apoE 等受体介导某些脂质从细胞内转运至细胞外。尚未确定血浆代谢物的 GWAS 鉴定出 ABCA7 基因位点与 Abca7-/- 小鼠的某些神经酰胺物种的显着关联。大脑发现包括神经酰胺在内的几种脂质类别的失调，这与认知功能受损相一致，这表明这些脂质在记忆和认知中发挥着功能作用。虽然 ABCA1 也在大脑中表达，但 ABCA1 和 ABCA 7 的细胞表达是不同的。 ABCA1 的遗传变异在人群水平上不具有相同的 AD 风险，因此，该提议指出，ABCA7 与 ABCA1 不同，易位并促进特定脂质的细胞流出。特定脑细胞类型中的 AD 保护性物质，ABCA 活性降低会导致有毒脂质物质的细胞积累，从而导致神经细胞功能障碍和 AD。确定三种不同 iPSC 衍生脑细胞（神经元、小胶质细胞和星形胶质细胞）中受 ABCA7 删除（与 ABCA1 相比）影响的特定脂质种类，并确定 ABCA 7 删除对 iPSC 的 AD 相关功能的影响衍生的脑细胞；2) 鉴定在脂质转位酶活性特异性方面将 ABCA7 与 ABCA1 区分开来的 ABCA7 蛋白结构域；3) 表征与 AD 显着相关的天然存在的 ABCA7 编码变体的功能效应。