Pathogenic mechanisms of ABCA7 in Alzheimer's disease

ABCA7在阿尔茨海默病中的发病机制

• 批准号: 9221000
• 负责人: Takahisa Kanekiyo
• 金额: $ 23.48万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221000
• 关键词: 3-Dimensional; ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Abeta synthesis; Address; Affect; African American; Age; Alpha Cell; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Brain; Cell Line; Cell model; Cells; Cellular Membrane; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Dementia; Deposition; Development; Diagnosis; Dimensions; Disease; Elderly; Family; Fluorescence-Activated Cell Sorting; Functional disorder; Genes; Genetic; Goals; Homeostasis; Human; Impaired cognition; In Vitro; Individual; Inflammatory Response; Integral Membrane Protein; Introns; Knock-out; Knockout Mice; Late Onset Alzheimer Disease; Link; Lipids; LoxP-flanked allele; Mediating; Membrane; Meta-Analysis; Metabolism; Microglia; Modeling; Mus; Mutation; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phagocytosis; Population; Process; Risk; Role; Susceptibility Gene; System; Tamoxifen; Technology; Therapeutic; Therapeutic Intervention; Tissues; Variant; amyloid pathology; amyloid precursor protein processing; base; brain cell; cell type; cognitive function; disorder risk; experimental study; familial Alzheimer disease; gamma secretase; genetic variant; genome wide association study; in vivo; in vivo Model; induced pluripotent stem cell; insight; lipid metabolism; lipophilicity; loss of function; macrophage; mild cognitive impairment; mind control; mouse model; neuroinflammation; novel; presenilin-1; promoter; synaptic function; transcriptome; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT MAYO CLINIC JACKSONVILLE ATP-binding cassette transporter A7 (ABCA7) gene variants are strongly associated with the risk of developing late-onset Alzheimer's disease (AD), which is the leading cause of dementia in the elderly. ABCA7 belongs to the ABC transporter family regulating distribution of lipids and other lipophilic molecules across cellular membranes. ABCA7 expression is abundant in the brain, particularly in neurons and microglia. Thus, a better understanding of the cell type-specific functions of ABCA7 is crucial for addressing the disease mechanisms. Because loss-of-function variants in ABCA7 have recently been demonstrated to increase AD risk, we hypothesize that ABCA7 deficiency contributes to the development and progression of AD via different pathways specific to each cell type. Given that ABCA7 levels in the brain are the highest in neurons followed by microglia, this proposal specifically focuses on the ABCA7-mediated pathways in these two cell types. We will perform single-cell type transcriptome analyses targeting neurons and microglia in control and conventional ABCA7 knockout mice. This systems-based approach should identify novel ABCA7-regulated genes/networks that modulate brain homeostasis and AD-related pathways. The results obtained through this approach will be validated not only in mouse primary cultures but also in human cells derived from induced pluripotent stem cells (iPSCs). Using Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 gene editing technology, ABCA7 knockout and haploinsufficient iPSC lines will be generated that model ABCA7 loss-of-function variants. Furthermore, we will investigate ABCA7 functions in neurons and microglia using unique tamoxifen-inducible, cell type-specific ABCA7 knockout mice through the Cre ER-loxP system with or without the background of amyloid pathology. We propose two specific aims. In Aim 1, we will define cell type-specific ABCA7-regulated pathways in neurons and microglia. In Aim 2, we will examine how the loss of function of ABCA7 impacts AD-related pathways using conditional mouse models. Collectively, these studies should provide novel mechanistic insight into how the loss of ABCA7 function in neurons or microglia impacts the risk for AD and has the potential to define novel targets for AD therapy.

项目摘要/摘要 杰克逊维尔梅奥诊所 三磷酸腺苷结合盒转运体A7(ABCA7)基因变异与发病风险密切相关 晚发性阿尔茨海默病(AD)，这是导致老年人痴呆症的主要原因。ABCA7属于 ABC转运蛋白家族调节脂类和其他亲脂分子在细胞内的分布 膜。ABCA7在大脑中大量表达，特别是在神经元和小胶质细胞中。因此，一个更好的 了解ABCA7特定细胞类型的功能对于解决疾病机制至关重要。 由于ABCA7中的功能缺失变体最近被证明会增加AD风险，我们 假设ABCA7缺乏通过不同的途径参与AD的发生和发展 每种细胞类型特有的通路。鉴于ABCA7在大脑中的水平在神经元中最高，其次是 小胶质细胞，这项建议特别关注ABCA7在这两种细胞类型中的介导途径。我们会 进行单细胞型转录组分析，针对对照组和常规组的神经元和小胶质细胞 ABCA7基因敲除小鼠。这种基于系统的方法应该识别新的ABCA7调控的基因/网络 调节大脑的动态平衡和AD相关的通路。通过这种方法获得的结果将是 不仅在小鼠原代培养中得到验证，而且在诱导多能干细胞来源的人类细胞中也得到验证 细胞(IPSCs)。使用簇状规则间隔短回文重复序列(CRISPR)/Cas9基因编辑 将产生ABCA7模型技术、ABCA7基因敲除和单倍体不足的IPSC系 丧失功能的变种。此外，我们将研究ABCA7在神经元和小胶质细胞中的功能 独特的他莫昔芬诱导的、细胞类型特异的ABCA7基因敲除小鼠，通过Cre ER-loxP系统与或 没有淀粉样变的背景。我们提出了两个具体目标。在目标1中，我们将定义单元格 神经元和小胶质细胞中特定类型的ABCA7调节通路。在目标2中，我们将研究如何损失 利用条件性小鼠模型，ABCA7的功能影响AD相关通路。总的来说，这些研究 应该为ABCA7在神经元或小胶质细胞中的功能丧失如何影响提供新的机制洞察力 AD的风险，并有可能为AD治疗定义新的靶点。