Mechanisms by which ABCA7 activity influences Alzheimer's Disease

阿尔茨海默病（AD）是痴呆症的最常见原因，影响近600万美国人，并且随着人口老龄化，患病率继续增加。AD导致进行性记忆丧失和认知障碍，最终可能导致完全无法执行日常功能。大脑是体内胆固醇含量最丰富、脂质最多样化的器官，它依赖于对脂质代谢和转运的严格调节来维持适当的神经信号转导和认知功能。几个大的GWAS已经将ABCA7基因位点与AD相关联，预测其变体具有与AD风险增加相关的功能降低。ABCA 7是ATP结合盒转运子亚家族A（ABCA）的成员，其功能被充分描述为膜磷脂（PL）移位酶和胆固醇和脂质从细胞流出的介质。最具特征的ABCA家族成员是ABCA 1，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和apoE中的作用已被广泛表征。ABCA 7与ABCA 1高度同源，提示ABCA？介导某些脂质从细胞内运输到细胞外，以响应apoA1和apoE等受体。然而，ABCA 7转运的特定脂质及其调节AD风险的机制尚未确定。血浆代谢物的GWAS确定了ABCA 7基因位点与某些神经酰胺物质的显著相关性。Abca7-/-小鼠脑的脂质组学分析揭示了包括神经酰胺在内的几种脂质类的调节异常，这与认知功能受损一致，表明这些脂质在记忆和认知中的功能作用。虽然ABCA 1也在大脑中表达，但ABCA 1和ABCA 7的细胞表达是不同的，并且ABCA 1的遗传变异在人群水平上不具有相同的AD风险。因此，它是假设在这一建议，ABCA 7，与ABCA 1，易位和促进细胞流出的特定脂质种类在特定的脑细胞类型中的AD保护的方式，并减少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。为了验证这一假设，提出了以下研究目标：1）确定ABCA 7缺失影响的特定脂质种类（与ABCA 1相比）在三种不同的iPSC衍生的脑细胞中（神经元、小胶质细胞和星形胶质细胞），并建立ABCA 7缺失对iPSC神经元衍生的脑细胞的AD相关功能的影响; 2）鉴定在脂质移位酶活性的特异性方面区分ABCA 7与ABCA 1的ABCA 7蛋白结构域; 3）表征与AD显著相关的天然存在的ABCA 7编码变体的功能效应。

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.