Acyl chain remodeling and regional lipid dysregulation in Alzheimer's disease

阿尔茨海默病中的酰基链重塑和区域脂质失调

• 批准号: 10358810
• 负责人: Laura Beth Johnson McIntire
• 金额: $ 40.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358810
• 关键词: ATP binding cassette transporter 1; Acyl Coenzyme A; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Animals; Apolipoprotein E; Atlases; Autopsy; Behavioral; Biological Markers; Biology; Brain; Brain region; Cerebrospinal Fluid; Coenzyme A Ligases; Cognitive; Cognitive deficits; Data; Data Set; Disease; Docosahexaenoic Acids; Electrophysiology (science); Electrospray Ionization; Emerging Technologies; Enzymes; Etiology; Explosion; Genes; Genetic; Genetic study; Genotype; Head; Hippocampus (Brain); Homeostasis; Human; Human Genetics; Image; Inositol; Investigation; Knock-in; Knock-out; Knowledge; Late Onset Alzheimer Disease; Lead; Learning; Lipids; Liquid substance; Long-Term Potentiation; Maps; Mass Spectrum Analysis; Mediator of activation protein; Memory; Metabolic; Metabolic Pathway; Methods; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Pathologic; Pathology; Pathway interactions; Performance; Phenocopy; Phosphatidylinositols; Phospholipase A2; Phospholipids; Phosphoric Monoester Hydrolases; Physiological; Plasma; Polyphosphates; Polyunsaturated Fatty Acids; Predisposition; Reporting; Resistance; Rodent; SYNJ1 gene; Support System; Synapses; System; Testing; Tg2576; Therapeutic; Transgenes; Variant; Wild Type Mouse; Work; abeta accumulation; age related; aging brain; base; biomarker discovery; brain cell; brain tissue; cell type; cholesterol transporters; cognitive function; embryonic stem cell; exhaustion; familial Alzheimer disease; genetic manipulation; genetic risk factor; genetic variant; genome wide association study; high risk; human data; human disease; lipid metabolism; lipid transport; lipidome; lipidomics; liquid chromatography mass spectrometry; metabolomics; mouse genetics; mouse model; overexpression; phospholipase D2; spatial memory; synthetic enzyme; therapeutic target; water maze

Accumulating data from human and mouse support the hypothesis that system level lipid disregulation is an early and critical factor in etiology and progression of Alzheimer's disease (AD). The explosion of 'omics methods in the past decade has resulted in a proliferation of various studies and data sets that interrogate specific regions of the brain. Using Imaging Mass Spectrometry (IMS), our preliminary studies have found regionally differential lipid composition in coronal sections from wild type mouse brain and a mouse model of Alzheimer's disease over expressing the amyloid precursor protein (APP) transgene. This regional lipid disregulation requires system-wide interrogation of lipid homeostasis which can singularly be accomplished with lididomics. A candidate based screen of lipid modifying enzymes in mouse embryonic stem cells for resistance to Aβ-triggered synapse loss, identified multiple metabolic enzymes which may be responsible for exit of polyunsaturated fatty acids (PUFA), specifically docosahexaenoic acid (DHA) from an acyl chain remodeling pathway, the Land's cycle. The Land's cycle has recently been identified to be dysfunctional in two animal models of AD. In the human context, DHA transport into the brain is aberrant by age 30, in carriers of a variant of apolipoprotein E (ApoE4) strongly associated with AD risk. Synthesis of these results with multiple hits from GWAS implicating lipid metabolism and transport, strongly support system-wide dyshomeostatis of acyl chain composition in the brain. However, the reports of regionally defined lipid composition are currently limited. We propose to test the hypothesis that acyl chain composition among multiple lipid classes is severely disregulated in brain regions known to be susceptible in AD including hippocampus and entorhynal cortex. Using IMS we will interrogate the lipid composition of mouse models of AD, Tg2576 and targeted replacement APOE mice as well as human brain tissue. We will then test the hypothesis that DHA accretion is a critical modifier of AD associated behavioral deficits and pathology in mouse models using knock-out lines of acyl- CoA synthetase 6 (Acsl6), a key mediator of DHA enrichment in the brain. We will generate new strains of Tg2576 and TRAPOE4 lacking Acsl6 and overexpressing Acsl6 to determine both necessity and sufficiency of DHA brain accretion for AD associated deficits. Finally, we will integrate and assemble our data into a publically available lipid brain atlas. These studies have potential to synthesize accumulating lipidomics data in aging and neurodegenerative disease. The use of spatial lipidomics at scale in the brain has not been yet be comprehensively accomplished, and is required for clear understanding of the basic metabolic pathways thus uncovering connectivity and functionality in the brain. Completion of these studies will represent compelling evidence for the critical nature of lipid composition in basic biology of AD and lead to new strategies for biomarker discovery as well as therapeutic targets.

来自人类和小鼠的累积数据支持这样一种假设，即系统水平的血脂失调是一种 阿尔茨海默病(AD)的病因和进展的早期和关键因素。“组学”的爆炸式增长 过去十年的方法导致了各种研究和数据集的激增，这些研究和数据集 大脑的特定区域。利用成像质谱学(IMS)，我们的初步研究发现 野生型小鼠脑冠状切片和小鼠脑缺血模型冠状切片中脂质成分的区域差异 阿尔茨海默病过度表达淀粉样前体蛋白(APP)转基因。这一地区的脂质 失调需要在系统范围内询问脂质稳态，而这一点可以单独完成 带着利尿剂。基于候选基因的小鼠胚胎干细胞脂质修饰酶的筛选 对β触发的突触丢失的抵抗力，鉴定出多种代谢酶可能与 多不饱和脂肪酸(PUFA)，特别是二十二碳六烯酸(DHA)从酰链上退出 重塑路径，土地的循环。最近发现，地球的周期在两个方面出现了障碍 AD的动物模型。在人类环境中，DHA在30岁之前进入大脑的运输是异常的，在A 载脂蛋白E(ApoE4)变异与AD风险密切相关。这些结果的综合具有多个 来自GWAS的HITS涉及脂类代谢和运输，强烈支持全系统的子宫肥胖症 大脑中的酰基链组成。然而，关于区域定义的脂类成分的报道目前 有限的。我们建议检验多个脂类之间的酰基链组成严重的假设 在已知AD易感的大脑区域，包括海马体和内胚脑皮质，表达紊乱。 使用IMS，我们将询问AD，Tg2576和靶向替换的小鼠模型的脂质成分 APOE小鼠以及人脑组织。然后，我们将检验DHA吸积是一个关键因素的假设 改良剂的AD相关的行为缺陷和病理模型中使用敲除的酰基- 辅酶A合成酶6(Acsl6)，大脑中DHA丰富的关键介体。我们将产生新的菌株 Tg2576和TRAPOE4缺失Acsl6并过度表达Acsl6以确定是否需要和充分 DHA脑积聚治疗AD相关缺陷。最后，我们将把我们的数据集成并组装成一个 公开发售的脂类脑图谱。这些研究有可能将积累的脂质组学数据合成在 衰老和神经退行性疾病。空间脂质组学在大脑中的规模化使用尚未得到 全面完成，是清楚了解基本代谢途径所必需的 揭示大脑的连通性和功能。完成这些研究将是令人信服的 AD基础生物学中脂类成分关键性质的证据，并导致治疗AD的新策略 生物标记物的发现以及治疗靶点。