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占痴呆症病例的 60-80%，影响 20% 以上。 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 AD 的发病、进展或严重程度仍然很大程度上未知。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，这表明需要寻找新的方法。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，指出了脂质相关的重要性然而，对脂质机制的研究。 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，导致少突胶质细胞的脂质失调负责在单细胞周围形成和维持髓鞘。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这些途径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异的 iPSC 衍生少突胶质细胞 (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具体目标是（1）表征脂质失调及其根本原因。 iOG 中带有 APOE4 变体或 ABCA7 中 LoF 变体的原因 (2) 来表征 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和此外，确定是否可以通过药物干预来挽救变异效应；有针对性地破坏失调途径中的单个基因将用于识别 (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。