Investigating cell-type specific convergence of APOE and ABCA7 lipid dysregulation in Alzheimer’s disease

研究阿尔茨海默病中 APOE 和 ABCA7 脂质失调的细胞类型特异性趋同

• 批准号: 10900993
• 负责人: Manolis Kellis
• 金额: $ 75.37万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10900993
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid; Apolipoprotein E; Autopsy; Axon; Biological Models; Brain; CRISPR interference; Candidate Disease Gene; Cell Nucleus; Cells; Cholesterol; Cholesterol Homeostasis; Coculture Techniques; Computing Methodologies; DNA Damage; Data; Defect; Dementia; Demyelinations; Disease; Disease Pathway; Drug Targeting; Female; Functional disorder; Gene Expression Profile; Genes; Genetic Transcription; Homeostasis; Human; Immunohistochemistry; Impaired cognition; Impairment; Individual; Induced pluripotent stem cell derived neurons; Intervention; Lead; Link; Lipids; Membrane Lipids; Memory Loss; Modeling; Molecular; Myelin; Myelin Sheath; Neurons; Oligodendroglia; Onset of illness; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Persons; Phenotype; Play; Population; Prefrontal Cortex; Process; Property; Proteins; Regulator Genes; Role; Sampling; Severities; Stress; Subcategory; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Variant; apolipoprotein E-4; brain cell; cell type; disorder control; endoplasmic reticulum stress; excitatory neuron; functional outcomes; genetic risk factor; genome wide association study; improved; induced pluripotent stem cell; insight; lipid metabolism; loss of function; male; myelination; novel strategies; pharmacologic; programs; risk variant; single-cell RNA sequencing; stem cell model; success; transcriptome; transcriptomics; treatment choice; white matter

Project Summary/Abstract Alzheimer’s disease (AD) is a progressive and fatal disorder characterized by memory loss and cognitive decline. It accounts for 60-80% of dementia cases and affects more than 20% of people over age 75. Several genetic risk factors have been identified, yet mechanisms linking them to AD onset, progression, or severity are still largely unknown. Therapeutic interventions, which have focused on improving pathological hallmarks of AD such as amyloid accumulation, have had only limited success, suggesting the need to identify new approaches. Lipid dysregulation has long been known to be important in AD, and damage to the lipid-rich myelin in white brain matter is emerging as a key pathology, pointing to the importance of lipid-related pathways as potential drug targets. However, studies of the mechanisms underlying lipid dysregulation in AD have been limited. This project seeks to identify commonalities in how AD risk variants in two different lipid-associated proteins, the lipid carrier ApoE and the trans- membrane lipid transporter ABCA7, lead to lipid dysregulation in oligodendroglia, the cells responsible for creating and maintaining the myelin sheath around neuronal axons. Single-cell RNAseq data from post-mortem brain samples will be used to identify transcriptional signatures that are present both in samples with the APOE4 variant and in samples with loss-of-function (LoF) variants in ABCA7 to reveal key lipid-related pathways that are perturbed by risk variants in either protein. The molecular and functional consequences of these pathway perturbations will then be explored in-depth in models based on induced pluripotent stem cells (iPSC) containing these risk variants. Co-culture systems of iPSC-derived oligodendrolia (iOG) and neurons (iN) have been shown to achieve axonal myelination and thus represent a fully tractable and modular model of neuron-oligodendrocyte interaction and oligodendrocyte functionality. The specific aims are (1) to characterize the lipid dysregulation and its underlying causes in iOG bearing the APOE4 variant or LoF variants in ABCA7; (2) to characterize the impact of the APOE4 variant or LoF variants in ABCA7 on myelination in iOG-iN co-cultures and to determine if the variant effects can be rescued by pharmacological intervention; in addition, targeted disruption of individual genes within the dysregulated pathways will be used to identify key regulatory genes involved in the variant effects; (3) to investigate if the transcriptional signatures found in samples with APOE4 or LoF variants in ABCA7 are also present in AD post- mortem brain samples that are non-carriers for APOE4 or ABCA7 LoF or bear other risk variants implicated in lipid metabolism, potentially identifying a sub-category of AD.

项目总结/摘要 阿尔茨海默病（AD）是一种进行性和致命性疾病，其特征在于记忆丧失， 认知能力下降它占痴呆症病例的60-80%，影响20%以上的人。 75岁以上的人。已经确定了几个遗传风险因素，但联系机制 他们对AD的发病、进展或严重程度仍知之甚少。治疗干预， 其重点在于改善AD的病理学特征，如淀粉样蛋白积累， 只有有限的成功，这表明需要确定新的方法。脂质 长期以来，人们已经知道调节异常在AD中是重要的，并且对富含脂质的髓磷脂的损伤是重要的。 白色脑物质正在成为一个关键的病理学，指出了脂质相关的重要性。 作为潜在的药物靶点。然而，对脂质代谢机制的研究 AD中的失调是有限的。该项目旨在确定AD如何 两种不同的脂质相关蛋白，脂质载体ApoE和反式- 膜脂质转运蛋白ABCA 7导致少突胶质细胞中的脂质失调 负责产生和维持神经元轴突周围的髓鞘。单细胞 来自死后大脑样本的RNAseq数据将用于识别转录特征 存在于APOE 4变体样本和功能丧失样本中 (LoF)ABCA 7的变异，以揭示受风险变异干扰的关键脂质相关途径 在任何一种蛋白质中。这些途径扰动的分子和功能后果 然后将在基于诱导多能干细胞（iPSC）的模型中深入探索 包含这些风险变量。iPSC衍生的少突胶质细胞（iOG）和 神经元（iN）已被证明可以实现轴突髓鞘形成，因此代表了一个完全的 神经元-少突胶质细胞相互作用和少突胶质细胞的易处理和模块化模型 功能.具体的目的是（1）表征脂质失调及其潜在的 携带APOE 4变体或ABCA 7中LoF变体的iOG中的原因;（2）表征 ABCA 7中APOE 4变体或LoF变体对iOG-iN共培养物中髓鞘形成的影响， 以确定是否可以通过药理学干预挽救变异效应;此外， 将使用失调途径中单个基因的靶向破坏来鉴定 参与变异效应的关键调控基因;（3）研究转录因子是否参与变异效应， 在ABCA 7中具有APOE 4或LoF变体的样品中发现的特征也存在于AD后 非APOE 4或ABCA 7 LoF携带者或具有其他风险的尸检脑样本 涉及脂质代谢的变异，可能识别AD的亚类。