Genetic and molecular correlates of white matter pathology in Alzheimers disease

阿尔茨海默病白质病理学的遗传和分子相关性

基本信息

批准号：
10539268
负责人：
Julia K Kofler
金额：
$ 60.73万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539268
关键词：
Acceleration Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Astrocytes Attention Autopsy Axon Biological Biology Biometry Blood Vessels Brain Brain region Candidate Disease Gene Cell physiology Cessation of life Complement DNA Damage Data Analyses Data Set Deposition Development Disease Disease Progression Functional disorder Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Transcription Genotype Growth Factor Human Image Analysis Impaired cognition Inflammation Investigation Knowledge Link Machine Learning Maintenance Measures Mediator Methods Microscopic Molecular Myelin Nerve Degeneration Neuroglia Neurons Oligodendroglia Optics Pallor Pathology Pathway Analysis Phenotype Population Process Reporting Research Research Design Research Personnel Role SNP array Sex Differences Stains Stratification Structure Synapses Techniques Testing Therapeutic Therapeutic Intervention Tissue Sample White Matter Disease White Matter Hyperintensity abeta accumulation brain tissue burden of illness cell population study cell type cohort design digital digital imaging endophenotype experimental study genetic variant genome wide association study gray matter human tissue hyperphosphorylated tau hypoperfusion immunohistochemical markers inflammatory marker insight interest ischemic injury nano-string neuroimaging neuropathology new therapeutic target novel novel marker protein aggregation regional difference risk variant sex tau Proteins tau-1 tool trait transcriptome sequencing transcriptomics white matter whole slide imaging

项目摘要

PROJECT SUMMARY: Although Alzheimer's disease (AD) is typically defined by the accumulation of beta- amyloid and hyperphosphorylated tau proteins, synaptic loss and neuronal degeneration, the disease is not restricted to the gray matter. Neuroimaging and neuropathological studies have documented a significant loss of white matter in AD, which begins early in the disease course and is correlated with cognitive decline. In addition to contributions of hypoperfusion-related ischemic injury and neurodegeneration-associated axonal loss, emerging evidence indicates a decline and dysfunction of oligodendrocyte populations as additional factors in this multifactorial white matter disease process. Oligodendrocytes are the most abundant glial cell type in the brain, but are the least studied cell population in the context of neurodegeneration despite their vital role for myelin maintenance and neuronal support. With the increasing recognition of the role of myelin in AD, it becomes important to understand the genetic and molecular factors that link oligodendrocytes to the AD process. Our knowledge about genetic variants contributing to overall AD risk and influencing AD-associated endophenotypes is accelerating. Our proposal is designed to bring these two lines of investigation together and begin to explore genetic modifiers of oligodendrocyte and myelin abnormalities in AD and underlying molecular mechanisms using a quantitative trait approach of neuropathologically defined myelin endophenotypes. The central hypothesis of our proposal is that loss of myelin integrity and oligodendrocyte dysfunction in AD are associated with genetic variants and molecular changes. We will test this hypothesis by first performing genome-wide association studies (GWAS) of white and gray matter neuropathological endophenotypes in human postmortem brain tissue samples and will then conduct bulk and spatially defined gene expression studies to explore underlying molecular mechanisms. Our experiments are divided into two specific aims: Aim 1) To determine genetic modifiers of myelin and oligodendrocyte pathologies in AD. Aim 2) To determine associations between white matter gene expression changes and white matter pathologies in AD. The above aims benefit from the tight integration and leveraging of a diverse group of investigators with expertise in the neuropathology of AD and digitally quantified pathology endophenotypes (PI Kofler), AD- associated oligodendrocyte pathology (Co-I Herrup), GWAS data analysis (Co-Is Kamboh and Fan), biostatistical analysis of transcriptomics datasets (Co-I Ding) and digital image analysis and machine learning (Co-I Pearce). Upon completion of our proposed studies, we will have identified novel candidate genes as mediators of myelin pathology in AD, increased our understanding about the biology underlying their linkage to AD and revealed novel targets for therapeutic interventions. As our study design includes separate analyses of gray and white matter regions and stratification by sex, we will have further delineated regional and sex- specific differences in myelin and oligodendrocyte pathobiology in the context of AD.

项目摘要：虽然阿尔茨海默氏病 (AD) 通常是由 β- 淀粉样蛋白和过度磷酸化的 tau 蛋白、突触损失和神经元变性，这种疾病不是仅限于灰质。神经影像学和神经病理学研究记录了显着的损失 AD 中白质的变化，在病程早期就开始出现，并与认知能力下降相关。在除了低灌注相关的缺血性损伤和神经退行性变相关的轴突的贡献之外损失，新出现的证据表明少突胶质细胞群的减少和功能障碍作为额外的这种多因素白质疾病过程中的因素。少突胶质细胞是最丰富的神经胶质细胞类型，但在神经退行性变的背景下研究最少的细胞群，尽管它们至关重要髓磷脂维持和神经元支持的作用。随着人们越来越认识到髓磷脂在 AD 中的作用，了解少突胶质细胞与 AD 之间的遗传和分子因素变得非常重要过程。我们对导致 AD 整体风险和影响 AD 相关疾病的基因变异的了解内表型正在加速。我们的建议旨在将这两条调查线结合起来开始探索 AD 中少突胶质细胞和髓磷脂异常的遗传修饰以及潜在的分子使用神经病理学定义的髓磷脂内表型的数量性状方法的机制。我们提案的中心假设是髓磷脂完整性和少突胶质细胞的丧失 AD 的功能障碍与遗传变异和分子变化有关。我们将测试这个首先对白质和灰质进行全基因组关联研究（GWAS）的假设人类死后脑组织样本中的神经病理学内表型，然后进行批量和空间定义的基因表达研究以探索潜在的分子机制。我们的实验是分为两个具体目标：目标 1) 确定髓磷脂和少突胶质细胞的遗传修饰剂 AD 中的病理学。目标 2) 确定白质基因表达变化与 AD 中的白质病理。上述目标得益于不同研究人员群体的紧密整合和利用 AD 神经病理学和数字量化病理内表型 (PI Kofler) 方面的专业知识，AD- 相关少突胶质细胞病理学 (Co-I Herrup)、GWAS 数据分析 (Co-Is Kamboh 和 Fan)、转录组数据集的生物统计分析（Co-I Ding）以及数字图像分析和机器学习（Co-I 皮尔斯）。完成我们提出的研究后，我们将确定新的候选基因： AD 中髓磷脂病理学的调节因子，增加了我们对它们与 AD 髓磷脂病理学联系的生物学基础的理解 AD 并揭示了治疗干预的新目标。由于我们的研究设计包括单独的分析灰质和白质区域以及按性别分层，我们将进一步划分区域和性别- AD 背景下髓磷脂和少突胶质细胞病理学的具体差异。