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: 10685399
• 负责人: Laura Beth Johnson McIntire
• 金额: $ 37.69万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685399
• 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; Homeostasis; Human; Human Genetics; Inositol; Investigation; Knock-in; Knock-out; Knowledge; Late Onset Alzheimer Disease; Learning; Lipids; Liquid substance; Long-Term Potentiation; Maps; Mass Spectrum Analysis; Mediator; Memory; Metabolic; Metabolic Pathway; Methods; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Pathologic; Pathology; Pathway interactions; Performance; Phase; Phenocopy; Phosphatidylinositols; Phospholipase A2; Phospholipids; Phosphoric Monoester Hydrolases; Physiological; Plasma; Polyphosphates; Polyunsaturated Fatty Acids; Predisposition; Proliferating; Reporting; Resistance; Rodent; SYNJ1 gene; Support System; Synapses; System; Testing; Tg2576; Therapeutic; Transgenes; Variant; Wild Type Mouse; Work; abeta accumulation; age related; aging brain; apolipoprotein E-4; biomarker discovery; brain cell; brain tissue; cell type; cholesterol transporters; cognitive function; embryonic stem cell; 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; mass spectrometric imaging; 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系统水平脂质失调是一种高脂血症的假说。 阿尔茨海默病（AD）是阿尔茨海默病（Alzheimer's disease，AD）发病的早期和关键因素。经济学的爆炸 在过去的十年中，方法导致了各种研究和数据集的激增， 大脑的特定区域。使用成像质谱（IMS），我们的初步研究发现， 野生型小鼠脑冠状切片中的区域差异脂质组成和 阿尔茨海默病过度表达淀粉样前体蛋白（APP）转基因。这种局部脂质 失调需要对脂质稳态进行系统范围的询问， 用利地多明。小鼠胚胎干细胞中脂质修饰酶的候选筛选 对Aβ触发的突触丢失的抵抗，确定了可能负责 多不饱和脂肪酸（PUFA），特别是二十二碳六烯酸（DHA）从酰基链上脱离 重塑路径土地的循环土地的周期最近被确定为在两个功能失调， AD动物模型在人类的情况下，DHA进入大脑的运输在30岁时是异常的， 载脂蛋白E（ApoE 4）变体与AD风险密切相关。综合这些结果， 来自GWAS的涉及脂质代谢和转运的命中，强烈支持 大脑中的酰基链然而，目前关于区域性定义的脂质组成的报告 有限公司我们建议测试的假设，酰基链组成之间的多种脂质类是严重的， 已知在AD中易感的脑区域（包括海马体和内嗅皮层）中存在失调。 使用IMS，我们将询问AD、Tg 2576和靶向替代的小鼠模型的脂质组成。 APOE小鼠以及人脑组织。然后，我们将测试假设，DHA的增长是一个关键的 在小鼠模型中使用酰基- CoA合成酶6（Acsl 6），脑中DHA富集的关键介质。我们将培育新的 Tg 2576和缺乏Acsl 6和过表达Acsl 6的TRAPOE 4来确定重组的必要性和充分性。 DHA脑蓄积用于AD相关缺陷。最后，我们将集成并将我们的数据组装到一个 脑脂质图谱。这些研究有可能综合积累脂质组学数据， 衰老和神经退行性疾病。空间脂质组学在大脑中的大规模使用尚未得到证实。 全面完成，并需要清楚地了解基本代谢途径， 揭示大脑的连通性和功能。这些研究的完成将是令人信服的 在AD基础生物学中脂质组成的关键性质的证据，并导致新的策略， 生物标志物发现以及治疗靶点。