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：
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
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/10685399
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 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

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.

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。使用酰基敲除系对小鼠模型中 AD 相关行为缺陷和病理进行修饰 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缺乏Acsl6和过表达Acsl6以确定必要性和充分性 DHA 大脑增生可治疗 AD 相关缺陷。最后，我们将把我们的数据整合并组装成一个模型。这些研究有可能综合积累的脂质组学数据。空间脂质组学在大脑中的大规模应用尚未得到证实。全面完成，并且需要清楚地了解基本代谢途径，从而揭示大脑的连接性和功能性将是令人信服的。脂质成分在 AD 基础生物学中的关键性质的证据，并导致新的策略生物标志物的发现以及治疗靶点。