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

基本信息

批准号：
10624511
负责人：
Laura Beth Johnson McIntire
金额：
$ 41.57万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
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/10624511
关键词：
ATP binding cassette transporter 1 Acyl Coenzyme A Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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 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 mass spectrometric imaging metabolomics mouse genetics mouse model overexpression phospholipase D2 spatial memory synthetic enzyme therapeutic target water maze

项目摘要

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.

来自人类和小鼠的数据积累数据支持了系统水平脂质不处调的假设是一种阿尔茨海默氏病（AD）病因学和进展的早期和关键因素。 'omics的爆炸过去十年中的方法导致了各种研究和数据集的扩散大脑的特定区域。使用成像质谱法（IMS），我们的初步研究发现野生型小鼠脑的冠状切片和小鼠模型的区域差异脂质组成阿尔茨海默氏病在表达淀粉样蛋白前体蛋白（APP）转化而疾病。这种区域脂质不脱离需要对脂质稳态的全系统询问，这可以单一完成与lididomics。基于候选的脂质修饰酶在小鼠胚胎干细胞中的酶对Aβ触发的突触损失的抗性，确定了多种代谢酶多不饱和脂肪酸（PUFA）的出口，特别是酰基链中的二十二烯酸（DHA）改建路径，土地的周期。该土地的周期最近被确定为功能失调 AD的动物模型。在人类的背景下，DHA在30岁时进入大脑的异常载脂蛋白E（APOE4）的变体与AD风险密切相关。这些结果与多个结果合成 GWAS隐式脂质代谢和运输的命中，强烈支持全系统范围内的dyshomeostatis 大脑中的酰基链组成。但是，当前有区域定义的脂质成分的报告有限的。我们建议检验以下假设：多种脂质类别之间的酰基链组成严重在已知在包括海马和内纳尔皮质在内的广告中易感的大脑区域中没有调节。使用IMS，我们将询问AD，TG2576的鼠标模型的脂质组成和靶向替换 APOE小鼠以及人脑组织。然后，我们将检验以下假设，即DHA积聚是关键 AD相关行为的修饰符使用酰基的敲除线定义了小鼠模型中的病理学 COA合成酶6（ACSL6），大脑中DHA富集的关键介体。我们将产生新的菌株 TG2576和TRAPOE4缺少ACCSL6和过表达ACSL6，以确定必要和充分性 DHA脑积聚相关的缺陷。最后，我们将集成并将我们的数据集成到一个公开可用的脂质脑图集。这些研究有可能合成在衰老和神经退行性疾病。在大脑中大规模使用空间脂质组学的使用尚未全面完成，是对基本代谢途径的清晰理解所必需的揭示大脑中的连通性和功能。这些研究的完成将代表令人信服的脂质组成在AD基本生物学中的批判性质的证据，并导致新的策略生物标志物发现以及治疗靶标。