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.

项目概要/摘要 阿尔茨海默氏病 (AD) 是一种进行性致命性疾病，其特征是记忆丧失和 认知能力下降。它占痴呆症病例的 60-80%，并影响超过 20% 的人 75 岁以上的人。已经确定了一些遗传风险因素，但相关机制尚未确定 它们对 AD 发病、进展或严重程度的影响仍然很大程度上未知。治疗干预措施， 其重点是改善 AD 的病理特征，例如淀粉样蛋白积累， 只取得了有限的成功，这表明需要确定新的方法。脂质 长期以来人们都知道调节失调在AD中很重要，而富含脂质的髓鞘质的损伤 白脑物质正在成为一种关键的病理学，表明与脂质相关的重要性 途径作为潜在的药物靶点。然而，对脂质潜在机制的研究 AD 的失调是有限的。该项目旨在找出 AD 的共性 两种不同脂质相关蛋白的风险变异，脂质载体 ApoE 和反式 膜脂质转运蛋白 ABCA7，导致少突胶质细胞脂质失调 负责在神经元轴突周围形成和维持髓鞘。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 APOE4 变体样本和功能丧失样本中 ABCA7 中的 (LoF) 变异揭示了受风险变异干扰的关键脂质相关途径 在任一蛋白质中。这些通路扰动的分子和功能后果 随后将在基于诱导多能干细胞（iPSC）的模型中进行深入探索 包含这些风险变体。 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化，因此代表了完全 神经元-少突胶质细胞相互作用和少突胶质细胞的易于处理和模块化模型 功能。具体目标是（1）描述脂质失调及其潜在的特征 iOG 中携带 APOE4 变体或 ABCA7 中 LoF 变体的原因； (2) 表征 APOE4 变体或 ABCA7 中的 LoF 变体对 iOG-iN 共培养物中髓鞘形成的影响 确定是否可以通过药物干预来挽救变异效应；此外， 有针对性地破坏失调途径中的单个基因将用于识别 参与变异效应的关键调控基因； (3) 考察转录是否 在 ABCA7 中具有 APOE4 或 LoF 变体的样本中发现的特征也存在于 AD 后处理中。 非 APOE4 或 ABCA7 LoF 携带者或具有其他风险的尸检大脑样本 与脂质代谢有关的变异，有可能确定 AD 的一个子类别。