System biology approach to decode molecular mechanism of glucose metabolism in AD and dementia

项目总结/摘要 阿尔茨海默病（AD）和痴呆症影响全球5000万人，预计到2050年将增加两倍。AD 是第六大死亡原因，仅在美国就影响了500多万人。尽管作出了巨大努力， AD脑中的生物化学和细胞变化仍不完全清楚， 目前还没有治疗药物。然而，越来越多的研究揭示了破坏葡萄糖之间的联系， 代谢和神经元细胞死亡。高葡萄糖水平会增加脑细胞损伤， 促进了淀粉样蛋白斑块和tau蛋白缠结的形成，糖酵解的减少导致严重的 痴呆GLUT（葡萄糖转运蛋白）、SGLT（钠依赖性协同转运蛋白）和胰岛素的改变 信号通路在AD/痴呆的脑中的报道。然而，这些变化的后果 在大脑中的作用以及与外周葡萄糖代谢和AD/痴呆的关系仍然存在争议。 鉴于2型糖尿病在老年人中的高患病率（在美国为28%），这一主题是及时的， 对进一步深入了解有重要意义。因此，我们建议询问系统的分子机制 使用成熟的大型队列，英国生物库（n= 500，000），通过 全转录组关联研究（TWAS）和共表达网络生物途径分析， 蛋白质组学TWAS整合了GWAS和表达数量性状基因座（eQTL），提高了预测能力 基因表达水平，并使坚实的解释基因性状协会。我们有两个具体目标; 1)估计与AD/痴呆相关的预测葡萄糖代谢基因表达。我们将使用TWAS 通过大脑中的GLUT，SGLT和胰岛素信号通路以及整个基因组的分析方法， 所有组织使用PrediXcan算法，该算法使用GTEx RNA-seg和eQTL数据用于其模型开发。（二） 确定与AD/痴呆相关的葡萄糖代谢分子途径和靶点。了建设一 通过加权基因构建与葡萄糖代谢基因相关的蛋白质组学共表达网络 共表达网络分析（WGCNA），并提出了高度重要的枢纽模块和驱动蛋白， 阐明AD/痴呆的多层生物学和分子治疗靶点。我们的建议可以提供 提高对早期疾病发生和进展的认识的基础知识 AD/痴呆症，并争取可靠的分子靶点，以加速药物发现或再利用。

Project Summary/Abstract Alzheimer’s disease (AD) and dementia affect 50 million worldwide and numbers expected to triple by 2050. AD is the 6th leading cause of death and affects more than 5 million in the USA alone. Despite substantial efforts, the biochemical and cellular changes in the brain of AD remain incompletely understood and no disease- modifying drugs are available yet. However, a growing number of studies reveal a link between disrupted glucose metabolism and neuronal cell death in AD/dementia. High glucose levels increased brain cell damage and promoted the formation of amyloid plaques and tau tangles, and a reduction in glycolysis lead to severe form of dementia. The alteration of GLUT (Glucose transporter), SGLT (sodium-dependent co-transporters), and insulin signaling pathway were reported in the brain of AD/dementia. However, the consequences of these alterations in the brain and the association with peripheral glucose metabolism and AD/dementia remain controversial. Given the high prevalence of type 2 diabetes in the older adults (28% in the USA), this topic is timely and significant for further in-depth knowledge. Thus, we propose to interrogate the systemic molecular mechanism of glucose metabolism in AD/dementia using a well-established large cohort, UK biobank (n=500,000) via Transcriptome-Wide Association Study (TWAS) and co-expression network biological pathway analysis with proteomics. TWAS integrates GWAS and expression quantitative trait loci (eQTL) increasing the power to predict gene expression levels and to enable solid interpretations of gene-trait associations. We have two specific aims; 1) Estimate predicted glucose metabolism gene expressions associated with AD/dementia. We will use a TWAS approach via GLUT, SGLT, and insulin signaling pathways in the brain and whole genome-wide analysis across all tissues using PrediXcan algorithm which uses GTEx RNA-seg and eQTL data for its model development. 2) Determine glucose metabolism molecular pathways and targets associated with AD/dementia. We will construct co-expression networks of proteomics that are associated with glucose metabolism genes via Weighted Gene Co-expression Network Analysis (WGCNA) and present highly significant hub module and driver proteins to elucidate multi-layered biological and molecular therapeutic targets for AD/dementia. Our proposal can provide fundamental knowledge in enhancing the understanding of early disease initiation and progression of AD/dementia and to enlist reliable molecular targets for the acceleration of drug discovery or repurposing.