Role of TTYH1 in mobilizing lipids and ApoE in glia: Implications for brain aging and neurodegeneration

TTYH1 在神经胶质细胞动员脂质和 ApoE 中的作用：对大脑衰老和神经退行性变的影响

• 批准号: 10644705
• 负责人: Ching-On Wong
• 金额: $ 34.34万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 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/10644705
• 关键词: Acute; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Apolipoprotein E; Astrocytes; Autophagocytosis; Brain; Brain Diseases; Cellular biology; Ceramides; Coculture Techniques; Coupled; Cytosolic Phospholipase A2; Dementia; Disease; Drosophila genus; Dryness; Genes; Genetic Transcription; Health; Homeostasis; Homologous Gene; Human; Impairment; Knockout Mice; Late Onset Alzheimer Disease; Lipid Mobilization; Lipids; Lipoproteins; Mediating; Membrane; Metabolic Pathway; Metabolism; Modeling; Molecular; Molecular Genetics; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Orthologous Gene; Pathogenesis; Pathway interactions; Phospholipases A; Phospholipids; Process; Protein Isoforms; Role; Signal Pathway; Signal Transduction; Sphingolipids; Stress; Tauopathies; Testing; Weight; aging brain; brain cell; brain health; conditional knockout; experimental study; fly; functional outcomes; healthspan; in vivo; inhibition of autophagy; insight; lipid biosynthesis; lipid metabolism; lipidomics; model organism; mutant; novel; nutrient deprivation; response; therapeutic target; trafficking; transcriptomics

PROJECT SUMMARY Lipids occupy over half of the dry weight of human brain. Brain cells rely on lipid metabolism to meet energy needs, perform signaling functions, and regulate membrane integrity and dynamics. Alterations in lipidomic profiles have been observed in aging brains and in neurodegenerative diseases such as Alzheimer’s disease (AD) and related dementia (ADRD), suggesting that reprogramed lipid metabolic pathways may be involved in disease pathogenesis. Notably, APOE and other lipid metabolism related genes have been associated with late-onset AD. Despite these observations, how aberrant metabolism of certain lipid classes mechanistically contribute to brain cell malfunction remains largely undefined. We sought to identify molecular pathways pertinent to brain lipid metabolism by utilizing approaches that combine molecular genetics and omics. Our transcriptomic analysis identified Tweety Homolog 1 (TTYH1) whose expression in human brain highly correlates with APOE. Such correlation between TTYH1 and APOE is lost in astrocytes of AD patients. Using human primary astrocyte and Drosophila model, we found that TTYH1 and its fly ortholog are required for ApoE secretion. Cell biology experiments further suggest that TTYH1 and its ortholog are required for autophagy and lipid droplet (LD) breakdown in glia. Lipidomic analyses of drosophila brains and human astrocytes deficient in TTYH1 orthologs revealed altered phospholipid abundances indicative of elevated cytosolic phospholipase A2 (cPLA2) activity. These preliminary findings inform our overarching hypothesis that TTYH1 is essential for a novel pathway connecting glial LD breakdown to lipoprotein secretion. In aim 1, we will test if cPLA2-activating ceramide metabolites regulates LD breakdown in glia, and define the function of TTYH1 in this process. Aim 2 will elucidate the mechanism of how TTYH1 regulates lipoprotein secretion in astrocytes. The significance of TTYH1-mediated lipid mobilization in brain aging and ADRD will be evaluated in Aim 3. We will assess the functional outcomes of perturbing TTYH1 ortholog in drosophila models of aging and ADRD. We will also examine the role of glial TTYH1 on neuronal homeostasis using coculture of brain cells derived from Ttyh1 conditional knockout mice. In summary, the project will integrate molecular genetics and lipidomics to illuminate a novel lipid metabolic pathway that hinges on TTYH1 in brain aging and ADRD. Findings from this project will aid in defining whether TTYH1 and its associated molecular players can serve as therapeutic targets for treating neurodegeneration.

项目摘要 脂质占人脑干重的一半以上。脑细胞依靠脂质代谢来满足能量 需求，执行信号功能并调节膜完整性和动力学。脂质组学的改变 在衰老的大脑和神经退行性疾病（例如阿尔茨海默氏病）中已经观察到了特征。 （AD）和相关痴呆（ADRD），表明重编程的脂质代谢途径可能参与 疾病发病机理。值得注意的是，APOE和其他脂质代谢相关的基因与 晚发广告。尽管进行了这些观察，但某些脂质类别的异常代谢机理如何 导致脑细胞故障的贡献在很大程度上不确定。我们试图识别分子途径 通过使用结合分子遗传学和幻象的方法，与脑脂质代谢有相关的代谢。我们的 转录组分析确定了Tweety同源1（TTYH1），其在人脑中的表达高度高 与ApoE相关。 TTYH1和APOE之间的这种相关性在AD患者的星形胶质细胞中丧失。使用 人类主要的星形胶质细胞和果蝇模型，我们发现TTYH1及其苍蝇直系同源 Apoe分泌。细胞生物学实验进一步表明TTYH1及其直系同源 神经胶质中的自噬和脂质液滴（LD）分解。果蝇大脑和人类的脂质组分析 缺乏TTYH1直系同源物的星形胶质细胞揭示了磷脂抽象的改变，表明升高 胞质磷脂酶A2（CPLA2）活性。这些初步发现为我们的总体假设提供了 TTYH1对于将神经胶质LD分解与脂蛋白分泌的新型途径至关重要。在AIM 1中，我们 将测试CPLA2激活神经酰胺代谢物是否调节神经胶质的LD分解，并定义 在此过程中TTYH1。 AIM 2将阐明TTYH1如何调节脂蛋白分泌的机制 星形胶质细胞。 TTYH1介导的脂质动员在大脑衰老和ADRD中的重要性将在 AIM 3。我们将评估在衰老模型和 adrd。我们还将使用脑细胞共培养神经胶质TTYH1在神经元稳态上的作用 源自TTYH1条件敲除小鼠。总而言之，该项目将整合分子遗传学和 脂质组学阐明了一种新型的脂质代谢途径，该途径在脑衰老和ADRD中取决于TTYH1。 该项目的发现将有助于定义TTYH1及其相关的分子参与者是否可以作为 治疗神经退行性的治疗靶标。