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

• 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
• 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' s Disease; Alzheimer' s disease pathology; Alzheimer' 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

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.

项目概述：虽然阿尔茨海默病（AD）通常定义为β-淀粉样蛋白的积累， 淀粉样蛋白和过度磷酸化的tau蛋白，突触丢失和神经元变性，这种疾病不是 仅限于灰质神经影像学和神经病理学研究已经证明了一个显着的损失 AD患者的白色物质减少，这在病程早期开始，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变性相关的轴突损伤的贡献外， 损失，新出现的证据表明，少突胶质细胞群体的减少和功能障碍， 在这个多因素的白色疾病过程中的因素。少突胶质细胞是最丰富的神经胶质细胞 类型的大脑，但在神经退行性变的背景下研究最少的细胞群体，尽管他们的重要性， 髓鞘维持和神经元支持的作用。随着人们越来越认识到髓鞘在AD中的作用， 了解将少突胶质细胞与AD联系起来的遗传和分子因素变得重要 过程我们对遗传变异导致总体AD风险和影响AD相关 内表型正在加速。我们的建议旨在将这两条调查路线结合起来， 开始探索AD中少突胶质细胞和髓鞘异常的遗传修饰物以及潜在的分子生物学机制。 使用神经病理学定义的髓磷脂内表型的定量性状方法的机制。 我们建议的中心假设是髓鞘完整性的丧失和少突胶质细胞 AD中的功能障碍与遗传变异和分子变化有关。我们将测试这个 首先进行白色和灰质的全基因组关联研究（GWAS） 在人类死后脑组织样品中的神经病理学内表型，然后将进行批量和 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 分为两个具体的目的：目的1）确定髓鞘和少突胶质细胞的遗传修饰剂 AD中的病理目的2）确定白色物质基因表达变化与 AD中的白色物质病理。 上述目标得益于紧密整合和利用不同的调查人员， AD神经病理学和数字量化病理学内表型（PI Kofler）方面的专业知识， 相关少突胶质细胞病理学（Co-I Herrup），GWAS数据分析（Co-Is Kamboh和Fan）， 转录组学数据集的生物统计分析（Co-I Ding）和数字图像分析和机器学习 (Co-I皮尔斯）。在完成我们提出的研究后，我们将确定新的候选基因， 介导的髓鞘病理学在AD，增加了我们的理解，其背后的生物学联系， 并揭示了治疗干预的新靶点。由于我们的研究设计包括单独分析 灰色和白色物质区域和性别分层，我们将进一步划定区域和性别- AD背景下髓鞘和少突胶质细胞病理生物学的特定差异。