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.

尽管外周血中的脂质组学测定是相对完善的，但空间- 在大脑中解决脂质组学是新颖的。大量脂质组学研究揭示了脂质 在衰老和疾病的代谢，但这些变化的区域和细胞类型的特异性仍然存在 未解决的。特别是，考虑到大脑由多种谱系的多种细胞类型组成， 调节的空间组织和相互连接，这可能是脂质分布，代谢和失调 在大脑中的分布是不均匀的因此，我们建议提供这种不均匀性的地图， 脑组织将大大推动该领域的发展，因为它有一个普遍的参照物，就像 艾伦小鼠大脑图谱彻底改变了研究人员查询大脑中基因表达空间模式的能力。 个脑袋我们相信，脂质组学图谱将以类似的方式进行变革，特别是考虑到增加的 专注于神经退行性疾病中的脂质失调。我们将检验这样一个假设， 链重塑途径可能是代谢谱如脂肪酸代谢和 由基因ABCA 7、PICALM和BIN 1介导的功能效应， 与晚发性AD遗传风险相关。我们对磷脂酰肌醇代谢的持续研究和 包括Synaptojanin 1（Synj 1）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BIN 1，也被称为两性蛋白酶2，与Synj 1相互作用，并可能介导 磷酸肌醇信号传导。有趣的是，ABCA 7已被证明可以转运溶血磷脂酰胆碱（LPC）。 兰德循环和酰基链重塑的主要生化中间体。近日，ABCA 7 单倍体缺陷已显示破坏小胶质细胞功能。很明显，功能研究，以了解 磷脂区域脑分布、细胞特异性和在细胞特异性功能中的作用对于获得脑内磷脂含量是至关重要的。 了解这些基因以及AD的发病机制和疾病进展。最终，我们将 基于脑中失调并显示相关性（阳性或阴性）的脂质鉴定生物标志物 血浆中的失调，这在临床上是容易处理的。我们假设脂质的重编程 代谢很可能是基于土地循环的早期变化，酰基链重塑。这么早， 脂质谱中的立体改变的代谢转变最终可用于生物标志物或治疗药物。 AD中的目标发现。成功完成这些研究将导致系统范围内的生物学洞察， 脂质代谢对阿尔茨海默病的贡献以及脂质发现平台的验证， 可以应用于未来的生物标志物以及治疗靶点的开发研究。