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

• 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
• 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' s Disease; Alzheimer' s disease pathology; Alzheimer' 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

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.

项目摘要 阿尔茨海默氏病（AD）的发病机理仍然难以捉摸。载脂蛋白（APO）E4等位基因的继承 是偶发发作AD的最强遗传危险因素，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修改广告风险的机制不是 完全阐明，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。综合多摩斯研究一直表明脂质的牢固关联 具有AD表型和APOE4的途径会破坏/细胞间脂质稳态在细胞，类骨子， 和动物模型以及带有不同APOE等位基因或具有或 没有广告。有趣的是，新兴的证据表明，脂质/代谢改变的特定物种 亚细胞细胞器，特别是线粒体，导致神经毒性和神经变性。线粒体是 细胞的动力室，并提供了维持重要的细胞功能的能量。值得注意的是，大脑包含两个 线粒体的主要种群，该突触线粒体起源于神经元的突触。 以及源自神经元和神经胶质细胞体的非突触线粒体。脂质分析表明 突触和非突触线粒体具有不同的脂质特征来调节隔室能量 大脑中的代谢。重要的是，线粒体的功能障碍，尤其是突触线粒体，很好 被确定为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。 但是，APOE基因型是否在脑衰老过程中调节线粒体的脂肪组以及是否调节 线粒体脂质组的动态变化影响AD的进展是未知的。我们假设这一点 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特定目的，以使用小鼠模型和 人类大脑以及行为和病理方法的结合，再加上创新的目标 和公正的细胞，分子技术，包括脂质组学，转录组学和大脑清除和3D 成像。 AIM 1是评估APOE同工型对与线粒体脂肪组动力学相关的影响 人源化APOE4和APOE3小鼠的脑老化。目标2是阐明线粒体之间的关系 APP/PS1小鼠中认知缺陷和淀粉样病理学的脂质组动力学和淀粉样病理的进展。 AIM 3是 定义线粒体脂肪组与不同APOE同工型的相互作用及其与认知的关系 人类大脑的功能和AD病理。预计结果将发现线粒体的影响 脂质组动力学及其与APOE在大脑衰老和AD上的相互作用，并确定新的目标/途径 可以将其作为诊断生物标志物和/或用于击败AD的诊断生物标志物。