Brain lipids and AD

脑脂质与 AD

• 批准号: 10644643
• 负责人: Jinying Zhao
• 金额: $ 67.05万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644643
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Autopsy; Bioinformatics; Blood; Blood specimen; Brain; Brain Mapping; Cellular Membrane; Clinical; Cognition; Cognitive; Cognitive aging; Collection; Communities; Complex; Custom; Cytoplasmic Granules; DNA; DNA Methylation; Data; Dementia; Disease; Elderly; Freezing; Functional disorder; Genomics; Glycerophospholipids; Goals; Human; Impaired cognition; Individual; Knowledge; Libraries; Lipids; Longitudinal cohort; Mass Spectrum Analysis; Measures; Memory; Meta-Analysis; MicroRNAs; Molecular; Multiomic Data; Multivariate Analysis; Neurofibrillary Tangles; Pathogenesis; Pathologic; Pathology; Patients; Persons; Phenotype; Play; Population; Population Study; Prefrontal Cortex; Prevention; Prospective cohort; Regulation; Reporting; Role; Sample Size; Sampling; Senile Plaques; Signal Transduction; Specimen; Spectrometry; Spectrum Analysis; Sphingolipids; Synapses; Tauopathies; Techniques; Technology; Tissue Sample; Tissues; Variant; Work; aging brain; blood lipid; brain tissue; carrier status; cognitive testing; cohort; epidemiology study; epigenomics; genome wide association study; innovation; lipid metabolism; lipidome; lipidomics; multiple omics; neuroinflammation; neuropathology; novel therapeutics; religious order study; sex; tau Proteins; transcriptome sequencing; transcriptomics

Project Summary Alzheimer’s dementia (AD) affects over 35 million people worldwide, and this number is expected to triple by 2050. As early as a century ago, Alois Alzheimer noted three significant neuropathological features in the brain of AD patients: senile plaques, neurofibrillary tangles, and lipid granule accumulation. While senile plaques and neurofibrillary tangles are now widely accepted as hallmarks of AD pathology, and thus have been extensively studied, the role of lipid accumulation in AD pathogenesis has been less studied. Lipidomics is a new omics technique that can identify and accurately quantify hundreds to thousands of lipids in biospecimens in large- scale population studies. Using this technology, many lipid species have been reported to be associated with cognitive phenotypes and AD neuropathologies (e.g., amyloid-beta, tau tangles). However, several key knowledge gaps exist in this field. First, previous studies have largely focused on blood, but the brain lipidomic profile is likely different from that of blood. To date, little is known about the global lipid composition and individual lipid species that trigger neuropathologies in human AD brains. Second, of the few existing lipidomic studies in human AD brains, sample size was mostly small and results were inconsistent. Importantly, the coverage of brain lipidome (i.e., collection of all lipid species in brain) in previous studies was low, and thus many disease-related lipids have not been investigated. To date, a full spectrum of brain lipidome in relation to AD pathology is lacking, especially in large-scale epidemiological studies. Finally, the potential causal role of lipid regulation in brain aging and AD neuropathology remains largely unknown and unexplored. To address these important questions, we leverage the large-collection of postmortem brain tissue samples, the deep clinical and neuropathological phenotypes, and the rich brain omics data (e.g., genomics, epigenomics, and transcriptomics) in two community-based longitudinal cohorts of aging and dementia – the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Specifically, we will conduct the first comprehensive lipidomic profiling in 1,450 frozen dorsolateral prefrontal cortex (DLPFC) using the Metabolon’s Complex Lipid Panel (CLP), a mass spectrometry based platform that can identify and accurately quantify the absolute concentrations of up to 1,100 individual lipid species and 14 lipid classes in large-scale epidemiological studies. Our goals here are to 1) generate the first comprehensive reference map of brain lipidome in relation to Alzheimer’s dementia-phenotypes (Aim 1); 2) identify individual brain lipid species associated with AD neuropathologies and cognitive phenotypes (Aims 1 and 2); and 3) elucidate the potential causal role of altered brain lipid regulation in AD pathology (Aim 3). Such results will shed light on the mechanisms through which lipid accumulation in the aging brain affects AD pathology, and provide evidence for targeting lipid metabolism in developing novel therapeutics for AD prevention and treatment.

项目摘要 阿尔茨海默氏症的痴呆症（AD）在全球范围内影响超过3500万人，这一数字有望由 2050年。早在一个世纪以前，阿洛伊斯·阿尔茨海默氏症指出了大脑中的三个重要神经病理学特征 AD患者：老年斑块，神经原纤维缠结和脂质颗粒积累。而老年斑块和 神经原纤维缠结现在被广泛接受为AD病理的标志，因此已广泛地接受 研究了，脂质积累在AD发病机理中的作用较少。脂质组学是一种新的OMICS 可以识别并准确地量化数百万种脂质的技术 规模人群研究。使用这种技术，据报道许多脂质物种与 认知表型和AD神经病理学（例如，淀粉样蛋白，tau缠结）。但是，有几个关键 知识差距存在于该领域。首先，先前的研究主要集中在血液上，但脑脂肪组学 特征可能与血液不同。迄今为止，关于全球脂质成分和 在人类广告大脑中触发神经病理学的个别脂质物种。其次，在少数现有的脂肪组中 在人类广告大脑中的研究，样本量大多很小，结果不一致。重要的是， 在先前的研究中，脑脂肪组（即脑中所有脂质物种的收集）的覆盖范围很低，因此 尚未研究许多与疾病相关的脂质。迄今为止，与 缺乏AD病理学，尤其是在大型流行病学研究中。最后，潜在的因果作用 脑衰老和AD神经病理学中的脂质调节仍然很大未知且出乎意料。解决 这些重要的问题，我们利用了验尸后脑组织样品的大量收集，深处 临床和神经病理学表型以及丰富的大脑磁毛学数据（例如，基因组学，表观基因组学和 转录组学）在两个基于社区的纵向同龄人中的衰老和痴呆群中 - 宗教秩序 研究与繁忙记忆和老化项目（Rosmap）。具体来说，我们将进行第一个综合 1,450个冷冻的背额前额叶皮层（DLPFC）中的脂质组分析，使用它的复合物脂质 面板（CLP），一个基于质谱的平台，可以识别并准确量化绝对性 大规模流行病学中最多1,100种单独的脂质物种和14种脂质类别的浓度 研究。我们在这里的目标是1）生成第一个有关脑脂肪组的全面参考图 到阿尔茨海默氏症的痴呆 - 表型（AIM 1）； 2）确定与AD相关的单个脑脂质物种 神经病理学和认知表型（目标1和2）； 3）阐明改变的潜在因果作用 AD病理学中的脑脂质调节（AIM 3）。这样的结果将阐明 衰老大脑中的脂质积累会影响AD病理，并为靶向脂质代谢提供了证据 在开发用于预防和治疗的新型疗法中。