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

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）的发病机制至今仍不清楚。载脂蛋白E4等位基因的遗传 是散发性迟发性AD最强的遗传危险因素，而APOE 2等位基因具有保护作用， 最常见的APOE 3等位基因是中性的。虽然APOE 4改变AD风险的机制并不明确， 充分阐明，令人信服的证据表明，APOE 4的致病作用是由脂质介导的， 相关路径综合性多组学研究一致表明，脂质 途径与AD表型，APOE 4破坏细胞内/细胞间脂质稳态，类器官， 和动物模型以及来自携带不同APOE等位基因的个体的死后脑组织， 没有AD。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，导致神经毒性和神经变性。线粒体是 细胞的发电站，并提供能量来维持重要的细胞功能。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终扣 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分布， 大脑的新陈代谢。重要的是，线粒体，特别是突触线粒体的功能障碍， 被确定为AD进展中最早的缺陷之一。APOE 4与增加的 在各种模型和人类患者中，与APOE 3相比，线粒体结构和功能受损。 然而，APOE基因型是否在脑老化过程中调节线粒体脂质体， 线粒体脂质体的动态变化影响AD的进展是未知的。我们假设 线粒体脂质组学动力学及其与APOE 4的相互作用驱动致病性脑老化和AD。三 提出了独立但相互关联的具体目标来检验这一假设，使用小鼠模型和 人类大脑和行为和病理方法的结合，再加上创新的针对性 和无偏见的细胞，分子技术，包括脂质组学，转录组学，大脑清除和3D 显像目的1是评估APOE亚型对线粒体脂质动力学的影响， 人源化APOE 4和APOE 3小鼠的脑老化。目的二是阐明线粒体与线粒体膜的关系， 脂组学动力学以及APP/PS1小鼠中认知缺陷和淀粉样蛋白病理学的进展。目标3是 确定线粒体脂质体与不同APOE亚型的相互作用及其与认知功能的关系。 功能和AD病理学。这些结果有望揭示线粒体对人类大脑的影响。 脂质组学动力学及其与APOE的相互作用对脑老化和AD的影响，并确定新的靶点/途径 可以作为诊断生物标志物和/或用于治疗开发以击败AD。

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.