Mechanisms by which ABCA7 activity influences Alzheimer's Disease

阿尔茨海默病（AD）是痴呆症最常见的病因，影响着近600万美国人，随着人口老龄化，患病率继续增加。阿尔茨海默病会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。大脑是体内胆固醇含量最高、脂质最多样化的器官，依赖于脂质代谢和转运的严格调控来维持正常的神经信号转导和认知功能。几个大的GWAS已经将ABCA7基因位点与阿尔茨海默病联系起来，而预测功能降低的变异与阿尔茨海默病风险增加有关。ABCA7是atp结合盒转运蛋白亚家族a （ABCA）的成员，具有膜磷脂（PL）转位和细胞胆固醇和脂质外排介质的功能。最具特征的ABCA家族成员是ABCA1，其在细胞磷脂酰胆碱（PC）和胆固醇外排到细胞外受体载脂蛋白apoA1和apoE中的作用已被广泛表征。ABCA7与ABCA1高度同源，说明ABCA？介导某些脂质从细胞内到细胞外的转运，以响应apoA1和apoE等受体。然而，ABCA7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鉴定出ABCA7基因位点与某些神经酰胺种类有显著关联。Abca7-/-小鼠大脑的脂质组学分析显示，包括神经酰胺在内的几种脂质类失调与认知功能受损相吻合，表明这些脂质在记忆和认知中发挥功能作用。虽然ABCA1也在大脑中表达，但ABCA1和abca7的细胞表达不同，在人群水平上，ABCA1的遗传变异不会带来相同的AD风险。因此，本研究假设，与ABCA1相比，ABCA7以ad保护的方式在特定脑细胞类型中易位并促进特定脂质种类的细胞外排，从而降低ABCA？活性导致有毒脂质的细胞积聚，导致神经细胞功能障碍和AD。为了验证这一假设，我们提出了以下研究目标：1)确定三种iPSC衍生的脑细胞（神经元、小胶质细胞和星形胶质细胞）中ABCA7缺失（与ABCA1相比）对特定脂质种类的影响，并确定ABCA7缺失对iPSC衍生的脑细胞ad相关功能的影响；2)确定区分ABCA7和ABCA1的脂质转位酶活性特异性的ABCA7蛋白结构域；3)表征与AD显著相关的自然发生的ABCA7编码变异的功能影响。

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.