Brain glycosphingolipids and Alzheimer's disease

阿尔茨海默氏痴呆症（AD）影响全球超过3500万人，预计这一数字将增加近三倍 到2050年AD的临床特征是进行性认知能力下降;病理性AD的定义是淀粉样蛋白 大脑中的斑块和神经纤维缠结尽管付出了巨大的努力，我们对它的理解 病理生理学仍不完整。对潜在机制的透彻理解是先决条件 发现新的治疗靶点。鞘糖脂是一类特殊的膜脂 由连接到一个或多个碳水化合物的神经酰胺主链组成（即，聚糖）。GSL特别是 在脑发育、脑老化和神经退行性变中起重要作用。 然而，由于技术的限制，我们对大脑GSL的整体组成和结构的了解， 并且它们与AD病理学的关联仍然有限。改变GSL表达的机制 对AD的贡献也仍然是一个谜。最近，我们开发了几种新的技术来识别 和定量完整的GSL（聚糖和不同的脂质形式作为一个整体），以及用于GSL的合成 及其衍生物。我们还成功地在人类和小鼠脑组织中验证了这些方法 样品利用这些创新的技术，我们将测试的假设，改变表达的大脑GSL 与AD病理学有因果关系。我们的目标是生成第一个完整的大脑GSLome图谱 (i.e.,脑中的所有GSL），以鉴定与AD神经病理学相关的特定GSL（例如，淀粉样蛋白-β， 神经元缠结），并阐明通过改变GSL的表达因果关系的机制， 有助于AD病理学。为了实现这些目标，我们利用了大量的人类死后大脑 组织样本（背外侧前额叶皮层，DLPFC）在两个社区为基础的队列老化和痴呆： 宗教秩序研究（ROS）和拉什记忆和衰老项目（MAP）。深层临床和神经病理学 表型以及丰富的组学数据（例如，GWAS、DNA甲基化、RNA-seq、蛋白质组学）已经在 在两个队列中均可用。在目标1中，我们将生成第一个完整的大脑GSL组图谱，并确定特定的 与AD神经病理学相关的GSL。使用数据驱动和系统生物学方法，Aim 2将整合 脑GSLome数据与其他脑组学数据，包括基因组学（GWAS），表观基因组学（DNA甲基化， 组蛋白乙酰化和miRNA），转录组学（RNA-seq）和同一大脑皮层中的蛋白质组学（DLPFC）， 以破译改变的脑GSL因果地促成AD病理学的机制。目标3 采用以基因为中心的方法对果蝇AD模型中排名靠前的基因进行功能验证。等 这些结果将为AD病理学提供新的机制见解，并将为以下方面提供巨大的机会： 靶向GSL途径，开发用于AD治疗的新疗法。

Alzheimer’s dementia (AD) affects over 35 million people worldwide, and this number is expected to nearly triple by 2050. AD is clinically characterized by progressive cognitive decline; pathologic AD is defined by amyloid plaques and neurofibrillary tangles in the brain. Despite substantial effort, our understanding of its pathophysiology remains incomplete. A thorough understanding of the underlying mechanisms is a prerequisite for discovering novel therapeutic targets. Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone attached to one or more carbohydrates (i.e., glycans). GSLs are especially abundant in the brain and play important roles in brain development, brain aging and neurodegeneration. However, due to technical limitations, our knowledge about the global composition and structures of brain GSLs and their associations with AD pathology remain limited. The mechanisms through which altered GSL expression contributes to AD also remain an enigma. Recently, we have developed several novel technologies for identifying and quantifying intact GSLs (both glycan and diverse lipid forms together as a whole), and for synthesis of GSLs and their derivatives. We have also successfully validated these methods in both human and mouse brain tissue samples. Using these innovative techniques, we will test the hypothesis that altered expression of brain GSLs is causally implicated in AD pathology. Our objectives are to generate the first complete map of brain GSLome (i.e., all GSLs in brain), to identify specific GSLs associated with AD neuropathology (e.g., amyloid-β, neurofibrillary tangles), and to elucidate the mechanisms through which altered expression of GSLs causally contributes to AD pathology. To achieve these goals, we leverage a large collection of human postmortem brain tissue samples (dorsolateral prefrontal cortex, DLPFC) in two community-based cohorts of aging and dementia: Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Deep clinical and neuropathological phenotypes as well as rich omics data (e.g., GWAS, DNA methylation, RNA-seq, proteomics) are already available in both cohorts. In Aim 1, we will generate the first complete map of brain GSLome and identify specific GSLs associated with AD neuropathology. Using a data-driven and system biology approach, Aim 2 will integrate brain GSLome data with other brain omics data, including genomics (GWAS), epigenomics (DNA methylation, histone acetylation, and miRNA), transcriptomics (RNA-seq) and proteomics in the same brain cortex (DLPFC), to decipher the mechanisms through which altered brain GSLs causally contribute to AD pathology. Aim 3 employs a gene-centric approach to functionally validate the top-ranked genes in Drosophila model of AD. Such results will provide novel mechanistic insight into AD pathology and would offer immense opportunities for targeting the GSL pathways in developing novel therapeutics for AD treatment.