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

项目总结 阿尔茨海默病(AD)的发病机制仍不清楚。载脂蛋白E4等位基因的遗传 是散发性晚发性AD的最强遗传风险因素，而APOE2等位基因是保护性的， 最常见的APOE3等位基因是中性的。而APOE4改变AD风险的机制并不是 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。 相关的路径。综合性的多组学研究一直表明，脂类与 具有AD表型的通路以及APOE4扰乱细胞内/细胞间脂类物质的稳态， 动物模型以及携带不同载脂蛋白E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/代谢变化在 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 细胞的动力库，并提供维持重要细胞功能的能量。值得注意的是，Brain包含两个 线粒体的主要群体，即起源于神经元突触的突触线粒体 以及源自神经元和神经胶质细胞体的非突触线粒体。脂组分析表明 突触和非突触线粒体有不同的脂谱来调节脑室能量 大脑中的新陈代谢。重要的是，线粒体，特别是突触线粒体的功能障碍是很好的。 被确定为阿尔茨海默病进展中最早的缺陷之一。载脂蛋白E4与 与APOE3相比，不同模型和人类患者的线粒体结构和功能受损。 然而，载脂蛋白E基因是否调节脑老化过程中线粒体的脂质体，以及是否 线粒体脂质体的动态变化对AD进展的影响尚不清楚。我们假设 线粒体脂体动力学及其与APOE4的相互作用导致了致病的脑老化和AD。三 独立但又相互关联的特定目标被提出来检验这一假设，使用小鼠模型和 人脑和行为与病理相结合的方法，再加上创新的针对性 以及无偏见的细胞和分子技术，包括脂质组学、转录组学、脑透明和3D 成像。目的1是评估载脂蛋白E亚型对线粒体脂质体动力学的影响。 人源化APOE4和APOE3小鼠的脑老化。目的2是阐明线粒体之间的关系 脂体动力学与APP/PS1小鼠认知缺陷和淀粉样蛋白病理的进展。目标3是 不同载脂蛋白E亚型的线粒体脂体相互作用及其与认知功能的关系 人脑的功能和AD病理。预计结果将揭示线粒体的影响 脂体动力学及其与载脂蛋白E在脑老化和AD中的相互作用，并识别新的靶点/途径 这可以被用作诊断生物标记物和/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.