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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos 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

项目摘要

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.

项目摘要/摘要阿尔茨海默氏病（AD）是一种进行性和致命疾病，其特征是记忆力丧失和认知能力下降。它占痴呆症病例的60-80％，影响超过20％ 75岁以上的人。已经确定了几个遗传危险因素他们要发作，进展或严重程度仍然很大程度上是未知的。治疗干预措施，重点是改善AD的病理标志，例如淀粉样蛋白积累，仅取得了有限的成功，这表明需要识别新方法。脂质长期以来，众所周知，失调在AD中很重要，并且对脂质富髓磷脂的损害很重要白人脑物质正在成为关键病理，指出与脂质相关的重要性作为潜在药物靶标的途径。但是，研究脂质的机制广告中的失调受到限制。该项目旨在确定有关如何广告的共同点两种不同脂质相关蛋白的风险变体，脂质载体ApoE和Trans- 膜脂质转运蛋白ABCA7，导致少突胶质细胞的脂质失调，细胞负责创建和维护神经元轴突周围的髓鞘。单细胞来自验尸后大脑样本的RNASEQ数据将用于识别转录特征在具有APOE4变体的样品和功能丧失的样品中都存在（LOF）ABCA7中的变体以揭示与风险变体扰动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，将基于诱导多能干细胞（IPSC）的模型中深入探讨包含这些风险变体。 IPSC衍生的寡头（IOG）和神经元（in）已被证明可以实现轴突髓鞘形式，因此代表了完全神经元 - 寡糖的相互作用和少突胶质细胞的可疗法和模块化模型功能。具体目的是（1）表征脂质功能障碍及其基础在ABCA7中带有APOE4变体或LOF变体的IOG原因；（2）表征 ABCA7中APOE4变体或LOF变体对IOG-IN共培养和确定是否可以通过药物干预来挽救变异效应；此外，在失调途径内的单个基因的有针对性破坏将用于识别参与变异效应的关键调节基因；（3）调查转录是否在ABCA7中具有APOE4或LOF变体样品中发现的签名也存在于AD后。 Mortem脑样本是APOE4或ABCA7 LOF或承担其他风险的非载体在脂质代谢中实施的变体可能识别AD的子类别。