Mechanisms by which ABCA7 activity influences Alzheimer's Disease

阿尔茨海默病(AD)是导致痴呆症的最常见原因，影响着近600万美国人，而且随着人口老龄化，其患病率仍在不断上升。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高、脂质含量最丰富的器官，它依赖于对脂类代谢和运输的严格调控来维持适当的神经信号转导和认知功能。几个大的GWA已经将ABCA7基因与AD联系在一起，其变异被预测具有与AD风险增加相关的功能降低。ABCA7是三磷酸腺苷结合盒转运体A亚家族(ABCA)的成员之一，具有膜磷脂转位酶和细胞内胆固醇和脂质外流的中介作用。最具特征的ABCA家族成员是ABCA1，它在细胞磷脂酰胆碱(PC)和胆固醇外流到细胞外受体apoA1和apoE中的作用已被广泛研究。ABCA7与ABCA1高度同源，提示ABCA？调节某些脂类从细胞内到细胞外的转运，以响应载脂蛋白A1和载脂蛋白E等受体。然而，ABCA7转运的特定脂类及其调节AD风险的机制尚未建立。血浆代谢物研究发现ABCA7基因与某些神经酰胺类有显著的关联。ABCA7-/-小鼠大脑的脂质组谱显示，包括神经酰胺在内的几种脂质类别的调节失调，这与认知功能受损不谋而合，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ABCA7的细胞表达不同，ABCA1的遗传变异在人群水平上并不具有相同的AD风险。因此，本研究假设，与ABCA1相反，ABCA7以AD保护的方式移位和促进特定脑细胞类型中特定脂类的细胞外流，从而减少ABCA？活性导致有毒脂质物质的细胞积聚，导致神经细胞功能障碍和阿尔茨海默病。为了验证这一假说，提出了以下研究目标：1)确定ABCA7缺失(与ABCA1相比)在三个不同的IPSC衍生脑细胞(神经元、小胶质细胞和星形胶质细胞)中影响的特定脂类，并建立ABCA7缺失对IPSC衍生脑细胞AD相关功能的影响；2)确定区分ABCA7和ABCA1的脂质转移酶活性的ABCA7蛋白结构域；3)表征与AD显著相关的自然发生的ABCA7编码变体的功能影响。

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.