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: 10317926
• 负责人: Laura Beth Johnson McIntire
• 金额: $ 0.96万
• 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: 2021-09-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317926
• 关键词: 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; Behavior; Behavioral; Biological Markers; Biology; Brain; Brain region; Cerebrospinal Fluid; Coenzyme A Ligases; Cognitive; Cognitive deficits; Data; Data Set; Defect; 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; Knock-in; 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; 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; neuroinflammation; overexpression; phospholipase D2; spatial memory; synaptic function; 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 overexpression of acyl- CoA synthetase 6 (Acsl6), a key mediator of DHA enrichment in the brain. We will generate new strains of Tg2576 and TRAPOE4 overexpressing Acsl6 to determine sufficiency of DHA brain accretion to ameliorate AD associated deficits in behavior, synaptic function, pathology and neuroinflammation. 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.

积累的人类和小鼠数据支持这样的假设：系统水平脂质失调是一种 阿尔茨海默病 (AD) 病因学和进展的早期和关键因素 “组学”的爆炸式增长。 过去十年中的方法导致了各种研究和数据集的激增，这些研究和数据集质疑 我们的初步研究发现，大脑的特定区域。 野生型小鼠大脑和小鼠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。 失调需要对脂质稳态进行全系统检查，这可以单独完成 小鼠胚胎干细胞中基于候选脂质修饰酶的筛选。 对 Aβ 触发的突触损失的抵抗，确定了多种代谢酶可能是造成这种情况的原因 多不饱和脂肪酸 (PUFA)，特别是二十二碳六烯酸 (DHA) 从酰基链中排出 重塑途径，土地循环最近被确定为两个功能失调的地方。 AD 动物模型中，DHA 携带者在 30 岁时大脑中的转运出现异常。 载脂蛋白 E (ApoE4) 的变体与 AD 风险密切相关。 GWAS 的命中表明脂质代谢和运输，有力地支持了全系统的动态平衡失调 大脑中的酰基链组成然而，目前关于区域定义的脂质组成的报告。 我们建议检验多种脂质类别中酰基链组成严重受限的假设。 已知易患 AD 的大脑区域失调，包括海马体和内嗅皮层。 使用 IMS，我们将询问 AD、Tg2576 和靶向替代小鼠模型的脂质组成 然后我们将测试 APOE 小鼠和人类脑组织的假设，即 DHA 积累是一个关键因素。 使用酰基过度表达来修饰小鼠模型中与 AD 相关的行为缺陷和病理学 CoA 合成酶 6 (Acsl6)，大脑中 DHA 富集的关键介质我们将产生新的菌株。 Tg2576 和 TRAPOE4 过表达 Acsl6 以确定 DHA 脑积聚是否足以改善 AD 最后，我们将整合行为、突触功能、病理学和神经炎症方面的相关缺陷。 并将我们的数据汇总成公开的脂质脑图谱，这些研究有潜力进行综合。 积累衰老和神经退行性疾病中的脂质组学数据大规模使用空间脂质组学。 大脑还没有完全完善，还需要对事物有清晰的认识 基本代谢途径，从而揭示大脑中的连接性和功能。 研究将为 AD 和 AD 基础生物学中脂质成分的关键性质提供令人信服的证据 导致生物标志物发现和治疗靶点的新策略。