Brain lipids and AD

项目摘要 阿尔茨海默氏症(AD)影响着全球超过3500万人，预计到2019年这一数字将增加两倍 2050年。早在一个世纪前，阿洛伊斯·阿尔茨海默就注意到大脑中有三个重要的神经病理特征 AD患者：老年斑、神经原纤维缠结、脂质颗粒堆积。而老年斑块和 神经原纤维缠结现在被广泛认为是AD病理的标志，因此已经被广泛接受 已有研究表明，脂质堆积在AD发病机制中的作用研究较少。脂质组学是一种新的组学 一种可以识别和准确定量大型生物标本中成百上千种脂质的技术- 大规模的人口研究。利用这项技术，据报道，许多类脂物种与 认知表型和阿尔茨海默病的神经病理(例如，淀粉样β蛋白、tau缠结)。然而，有几个关键 这一领域存在知识鸿沟。首先，以前的研究主要集中在血液上，但大脑脂肪组学 侧写很可能与血液的不同。到目前为止，人们对全球脂质成分和 在人类阿尔茨海默病大脑中引发神经病理的个别脂质物种。第二，在现存的少数几种脂肪体中 在人类阿尔茨海默病大脑的研究中，样本量大多很小，结果不一致。重要的是， 在以前的研究中，脑脂质体(即大脑中所有类脂物种的集合)的覆盖率很低，因此 许多与疾病相关的血脂还没有被研究。到目前为止，与脑内脂质体相关的全谱 AD病理学缺乏，尤其是在大规模的流行病学研究中。最后，潜在的因果关系作用 脑老化和AD神经病理中的脂质调节在很大程度上仍然是未知和未被探索的。致信地址 这些重要的问题，我们利用大量的死后脑组织样本，深部 临床和神经病理表型，以及丰富的脑组学数据(例如基因组学、表观基因组学和 转录学)在两个社区为基础的纵向队列的老龄化和痴呆-宗教秩序 研究和快速记忆与衰老项目(ROSMAP)。具体来说，我们将进行第一次全面的 1,450例冷冻前额叶背外侧皮质脂代谢复合体的研究 Panel(CLP)，一个基于质谱学的平台，可以识别和准确量化绝对 大规模流行病学中多达1,100个个体类脂物种和14个类脂类的浓度 学习。我们在这里的目标是：1)生成第一张全面的脑脂质体参考图 阿尔茨海默病--表型(目标1)；2)确定与阿尔茨海默病相关的个体脑脂类物质 神经病理学和认知表型(目标1和2)；以及3)阐明改变的潜在原因作用 AD病理中的脑脂调节(目标3)。这样的结果将阐明通过什么机制 衰老脑内脂质堆积影响AD病理，为脂类代谢靶向提供证据 开发防治阿尔茨海默病的新疗法。

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.