Spatial dysregulation of the lipidome in Alzheimers disease human and mouse brain

阿尔茨海默病人和小鼠大脑中脂质组的空间失调

• 批准号: 10516567
• 负责人: Laura Beth Johnson McIntire
• 金额: $ 70.93万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516567
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Animal Model; Animals; Apolipoprotein E; Atlases; Autopsy; Behavioral; Binding Proteins; Biochemical; Biological; Biological Assay; Biological Markers; Brain; Brain Diseases; Cells; Cerebrospinal Fluid; Characteristics; Clinic; Cognitive deficits; Data; Disease; Disease Progression; Docosahexaenoic Acids; Enrollment; Enzymes; Freezing; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Risk; Genetic study; Head; Hippocampus (Brain); Homeostasis; Human; Human Genetics; Image; In Situ; Inositol; Late Onset Alzheimer Disease; Lecithin; Lipids; Lysophosphatidylcholines; Manuscripts; Maps; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolism; Methods; Microglia; Mus; Neurodegenerative Disorders; Nonesterified Fatty Acids; PLCgamma2; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phenocopy; Phosphatidylethanolamine; Phosphatidylinositols; Phospholipase A2; Phospholipid Metabolism; Phospholipids; Phosphoric Monoester Hydrolases; Plasma; Play; Polyphosphates; Polyunsaturated Fatty Acids; Prefrontal Cortex; Preparation; Radiolabeled; Reporting; Research Personnel; Resolution; Role; SYNJ1 gene; Signal Transduction; Specificity; System; Testing; Tissues; Validation; Variant; abeta accumulation; age related; apolipoprotein E-4; base; biomarker development; brain tissue; cell type; cholesterol transporters; docosahexaenoylascorbic acid; entorhinal cortex; exhaustion; familial Alzheimer disease; fatty acid metabolism; frontal lobe; gene network; genetic risk factor; genetic variant; genome wide association study; human disease; immunocytochemistry; innovation; insight; lipid metabolism; lipidome; lipidomics; lysophosphatidylinositol; mass spectrometric imaging; metabolic profile; mild cognitive impairment; mouse model; multidimensional data; novel; peripheral blood; phospholipase D2; public database; religious order study; tau Proteins; therapeutic target; tissue processing; transcriptomics

Whereas lipidomics assays in peripheral blood are relatively well-established, the application of spatially- resolved lipidomics in the brain is novel. Bulk lipidomics studies have revealed potential differences in lipid metabolism across aging and disease, but the regional and cell type-specificity of these changes remains unresolved. In particular, given that the brain comprises numerous cell types of multiple lineages with tightly regulated spatial organization and inter-connections, it is likely the lipid profiles, metabolism, and dysregulation are all dramatically non-uniform across the brain. Thus, we propose to provide a map of this non-uniformity in brain tissue would move the field forward substantially in terms of having a universal reference, much as the Allen mouse brain atlas revolutionized researchers' ability to query spatial patterns of gene expression in the brain. We believe that a lipidomics atlas will be transformative in a similar way, especially given the increased focus on lipid dysregulation in neurodegenerative disease. We will test the hypothesis that deficits in the acyl chain remodeling pathway may underlie the changes in metabolic profile such as fatty acid metabolism and functional effects mediated by genes ABCA7, PICALM and BIN1 which have recently been identified associated with Late Onset AD genetic risk. Our continuing studies on phosphoinositide metabolism and the gene network including Synaptojanin1 (Synj1) are highly relevant to PICALM, a phosphoinoistide binding protein, and BIN1, also known as amphiphysin2, which interacts with Synj1 and is likely to mediate phosphoinositide signaling. ABCA7 interestingly, has been shown to transport lysophosphatidylcholine (LPC) a major biochemical intermediate of the Land's cycle and acyl chain remodeling. Recently, ABCA7 haplodefeciency has been shown to disrupt microglia function. It is clear that functional studies to understand phospholipid regional brain distribution, cell specificity and roles in cell-specific functions are critical for gaining understanding of these genes as well as the pathogenesis and disease progression of AD. Ultimately, we will identify biomarkers based on lipids which are dysregulated in brain and show correlated (positive or negative) dysregulation in plasma, which is tractable in the clinic. We hypothesize that re-programming of lipid metabolism is likely to be based on early changes in the Lands Cycle, acyl chain remodeling. This early and stereotypically altered metabolic shift in the lipid profile could ultimately be used for biomarker or therapeutic target discovery in AD. Successful completion of these studies will lead to system-wide, biological insight into the contribution of lipid metabolism to Alzheimer's Disease and validation of a lipid discovery platform which can be applied to future studies for development of biomarkers as well as therapeutic targets.

虽然外周血中的脂质组学分析已经相对成熟，但空间- 在大脑中分解的脂类组学是新的。大量脂类组学研究揭示了脂类的潜在差异 跨年龄和疾病的新陈代谢，但这些变化的区域性和细胞类型特异性仍然存在 悬而未决。特别是，鉴于大脑由多种血统的多种细胞类型组成， 调节空间组织和相互联系，很可能是脂谱、新陈代谢和失调 在整个大脑中都是戏剧性的不一致。因此，我们建议在图中提供这种不一致性的地图 就拥有一个通用参考而言，脑组织将极大地推动磁场向前发展，就像 艾伦小鼠脑图谱彻底改变了研究人员查询基因表达的空间模式的能力 大脑。我们相信，脂质组学图谱将以类似的方式产生变革，特别是考虑到 关注神经退行性疾病中的脂质失调。我们将检验这一假设，即酰基中的赤字 链重塑途径可能是代谢谱变化的基础，如脂肪酸代谢和 新近发现的ABCA7、PICALM和BIN1基因介导的功能效应 与晚发性阿尔茨海默病遗传风险相关。我们对磷脂酰肌醇代谢的持续研究 包括Synaptojanin1(Synj1)在内的基因网络与PICALM高度相关，PICALM是一种磷酸肌醇结合蛋白 蛋白质，和BIN1，也被称为两栖物理蛋白2，它与Synj1相互作用，并可能介导 肌醇磷脂信号。有趣的是，ABCA7已被证明可以运输溶血磷脂酰胆碱(LPC)a 土地循环和酰链重塑的主要生化中间体。最近，ABCA7 单倍体缺陷已被证明会扰乱小胶质细胞的功能。显然，功能研究需要理解 磷脂在脑内的区域分布、细胞特异性和在细胞特异性功能中的作用是获得 了解这些基因以及阿尔茨海默病的发病机制和疾病进展。最终，我们会 根据大脑中调节失调并显示相关(正或负)的脂类确定生物标记物 血浆中的失调，这在临床上是可以治疗的。我们假设脂类的重新编程 新陈代谢很可能是基于Lands循环的早期变化，即酰链重塑。这么早，而且 类脂代谢的陈旧改变最终可用于生物标记物或治疗 AD中的目标发现。这些研究的成功完成将导致系统范围内的生物学洞察 脂代谢在阿尔茨海默病中的作用及脂类发现平台的验证 可应用于未来开发生物标记物以及治疗靶点的研究。