Impact of Mitochondrial Lipidomic Dynamics and its Interaction with APOE Isoforms on Brain Aging and Alzheimers Disease

线粒体脂质组动力学及其与 APOE 亚型的相互作用对脑衰老和阿尔茨海默病的影响

基本信息

批准号：
10645610
负责人：
LING LI
金额：
$ 66.46万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10645610
关键词：
APP-PS1 Acceleration Affect Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk American Amyloid deposition Amyloidosis Animal Model Astrocytes Autopsy Behavioral Brain Brain Diseases Cell Fractionation Cell Nucleus Cell model Cell physiology Cells Cerebrum Clinical Cognition Cognitive deficits Coupled Data Dementia Development Energy Metabolism Evaluation Family Genes Genotype Homeostasis Human Impaired cognition Impairment Individual Induced pluripotent stem cell derived neurons Knock-in Late Onset Alzheimer Disease Lead Lipids Literature Mediating Metabolic Mitochondria Modeling Molecular Molecular Target Mus Nerve Degeneration Neurobehavioral Manifestations Neuroglia Neurons Organelles Organoids Participant Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Phospholipase A2 Plasma Population Presynaptic Terminals Prevalence Protein Isoforms Research Severities Specimen Structure Synapses Technology Testing Three-Dimensional Imaging Tissue Sample Transgenic Organisms Wild Type Mouse acylcarnitine age related aging brain aging population amyloid pathology apolipoprotein E-3 apolipoprotein E-4 brain tissue cell type cognitive function diagnostic biomarker disease phenotype genetic risk factor human old age (65+)human tissue innovation lipidome lipidomics metabolomics middle age mitochondrial dysfunction mouse model multiple omics neuropathology neurotoxicity novel religious order study sex therapeutic development transcriptomics

项目摘要

PROJECT SUMMARY The pathogenesis of Alzheimer's disease (AD) remains elusive. Inheritance of the apolipoprotein (APO) E4 allele is the strongest genetic risk factor for sporadic late onset AD, whereas the APOE2 allele is protective and the most common APOE3 allele is neutral. While the mechanisms by which APOE4 modifies the risk of AD are not fully elucidated, compelling evidence indicates that the pathogenic effects of APOE4 are mediated by lipid- related pathways. Integrative multi-omics studies have consistently demonstrated the strong association of lipid pathways with AD phenotypes and that APOE4 disrupts intra/intercellular lipid homeostasis in cellular, organoid, and animal models as well as postmortem brain tissue from individuals carrying different APOE alleles with or without AD. Intriguingly, emerging evidence suggests that specific species of lipids/metabolic alterations in subcellular organelles, in particular mitochondria, lead to neurotoxicity and neurodegeneration. Mitochondria are the powerhouse of cells and provide the energy to sustain vital cellular functions. Notably, brain contains two major populations of mitochondria, the synaptic mitochondria that originate from the synaptic bouton of neurons and the non-synaptic mitochondria that originate from neuronal and glial cell bodies. Lipidomic analysis indicates that synaptic and non-synaptic mitochondria have distinct lipid profiles that regulate compartmental energy metabolism in the brain. Importantly, dysfunction of mitochondria, especially synaptic mitochondria, is well established as one of the earliest deficits in the progression of AD. APOE4 has been associated with increased impairment of mitochondrial structure and function compared with APOE3 in various models and human patients. However, whether APOE genotypes regulate the lipidome of mitochondria during brain aging and whether the dynamic changes of mitochondrial lipidomes affect the progression of AD are unknown. We hypothesize that mitochondrial lipidomic dynamics and its interaction with APOE4 drive pathogenic brain aging and AD. Three independent yet interrelated specific aims are proposed to test the hypothesis, using both mouse models and human brains and a combination of behavioral and pathological approaches, coupled with innovative targeted and unbiased cellular, molecular technologies, including lipidomics, transcriptomics, and brain clearing and 3D imaging. Aim 1 is to assess the impact of APOE isoforms on mitochondrial lipidomic dynamics associated with brain aging in humanized APOE4 and APOE3 mice. Aim 2 is to elucidate the relationship between mitochondrial lipidomic dynamics and the progression of cognitive deficits and amyloid pathology in APP/PS1 mice. Aim 3 is to define the interaction of mitochondrial lipidome with different APOE isoforms and its relation to cognitive function and AD pathology in human brains. The results are expected to uncover the impact of mitochondrial lipidomic dynamics and its interaction with APOE on brain aging and AD, and identify novel targets/pathways that can be harnessed as diagnostic biomarkers and/or for therapeutic development to defeat AD.

项目概要阿尔茨海默病（AD）的发病机制仍然难以捉摸。载脂蛋白 (APO) E4 等位基因的遗传是散发性迟发性 AD 的最强遗传风险因素，而 APOE2 等位基因具有保护性，并且最常见的 APOE3 等位基因是中性的。虽然 APOE4 改变 AD 风险的机制尚不清楚充分阐明的、令人信服的证据表明 APOE4 的致病作用是由脂质介导的相关途径。综合多组学研究一致证明脂质与 APOE4 破坏细胞、类器官、细胞内/细胞间脂质稳态和动物模型以及携带不同 APOE 等位基因的个体的死后脑组织没有广告。有趣的是，新出现的证据表明，特定种类的脂质/代谢改变亚细胞器，特别是线粒体，会导致神经毒性和神经变性。线粒体是细胞的动力室，提供维持重要细胞功能的能量。值得注意的是，大脑包含两个线粒体的主要群体，突触线粒体起源于神经元的突触纽带以及源自神经元和神经胶质细胞体的非突触线粒体。脂质组学分析表明突触和非突触线粒体具有不同的脂质谱来调节区室能量大脑中的新陈代谢。重要的是，线粒体，尤其是突触线粒体的功能障碍是很容易发生的。被认为是 AD 进展中最早的缺陷之一。 APOE4 与增加有关在各种模型和人类患者中，与 APOE3 相比，线粒体结构和功能受损。然而，APOE 基因型是否在大脑衰老过程中调节线粒体脂质组以及是否线粒体脂质组的动态变化对 AD 进展的影响尚不清楚。我们假设线粒体脂质组动力学及其与 APOE4 的相互作用驱动致病性脑衰老和 AD。三提出了独立但相互关联的具体目标来检验假设，使用小鼠模型和人脑以及行为和病理方法的结合，加上创新的有针对性的方法以及公正的细胞、分子技术，包括脂质组学、转录组学以及大脑清除和 3D 成像。目标 1 是评估 APOE 亚型对线粒体脂质组动力学的影响人源化 APOE4 和 APOE3 小鼠的大脑老化。目标2是阐明线粒体之间的关系 APP/PS1 小鼠的脂质组动力学以及认知缺陷和淀粉样蛋白病理学的进展。目标 3 是定义线粒体脂质组与不同 APOE 亚型的相互作用及其与认知的关系人脑的功能和 AD 病理学。预计结果将揭示线粒体的影响脂质组动力学及其与 APOE 对大脑衰老和 AD 的相互作用，并确定新的靶点/途径可以用作诊断生物标志物和/或用于治疗 AD 的开发。