HIV and cocaine use leads to loss of astrocyte neurotrophic support and impaired lipid homeostasis in the brain

HIV和可卡因的使用导致星形胶质细胞神经营养支持的丧失和大脑中脂质稳态的受损

基本信息

批准号：
10450981
负责人：
Dianne Teresa LANGFORD
金额：
$ 52.06万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2022-08-31
项目状态：
已结题

项目摘要

Summary Tight metabolic coupling between astrocytes and neurons involves astrocytes sensing neuronal stress and responding by taking up lipid-like particles containing excess peroxidated fatty acids (FA) generated during stress. During stressful conditions, the generation of reactive oxygen species (ROS) induce the peroxidation of FA in neurons. Neurons are highly sensitive to toxic peroxidated FA and unlike astrocytes, neurons have a low capacity to form lipid droplets (LD) to encase the toxic FA. Moreover, neuronal mitochondria are unable to efficiently consume FAs as an energy source. Thus, neurons expel lipid-like particles carrying the FAs. Astrocytes endocytose lipid-like particles with FA, deliver them to the ER for packaging into lipid droplets (LD) to protect the cell from the toxic FAs. LD also provide a conduit for delivery of FA to astrocyte mitochondria for use as an alternative energy source during stress. In normal conditions, astrocytes use glucose rather than FA as their main source of reserve energy under normal conditions. Metabolic coordination between astrocytes and neurons is critical for CNS functioning and lipid homeostasis. However, changes in astrocyte-neuron coupling for lipid metabolism in response to HIV and cocaine use is unknown. It is known that toxic, peroxidated fatty acids (FAs) produced and expelled by stressed neurons are transferred to astrocytic lipid droplets (LD) by lipoprotein particles. Astrocytes consume the FAs stored in LD via mitochondrial β-oxidation. Thus, metabolism of neuron-derived FA metabolism by astrocytes protects neurons from FA toxicity. Disruption of this tightly coordinated coupling to metabolize FAs likely contributes to the increased astrocytic energy metabolism and neuronal deficit reported during detrimental synergy between HIV infection and cocaine use.

概括星形胶质细胞和神经元之间的紧密代谢耦合涉及星形胶质细胞感知神经元应激并通过吸收产生的含有过量过氧化脂肪酸（FA）的类脂颗粒来做出反应在压力条件下，活性氧（ROS）的产生会导致神经元中 FA 的过氧化反应与有毒的过氧化 FA 高度敏感。星形胶质细胞、神经元形成脂滴 (LD) 来包裹有毒 FA 的能力较低。神经元线粒体无法有效消耗 FA 作为能量来源，因此神经元会排出。星形胶质细胞内吞带有 FA 的脂质样颗粒，将其递送至 ER 包装成脂滴 (LD)，以保护细胞免受有毒 FA 的侵害。用于将 FA 递送至星形胶质细胞线粒体，用作应激期间的替代能源。正常情况下，星形胶质细胞使用葡萄糖而不是FA作为其储备能量的主要来源正常情况下，星形胶质细胞和神经元之间的代谢协调对于中枢神经系统至关重要。然而，星形胶质细胞-神经元偶联对脂质代谢的影响。已知有毒的过氧化脂肪酸（FA）对艾滋病毒和可卡因使用的反应尚不清楚。由应激神经元产生和排出的脂质通过以下方式转移到星形细胞脂滴（LD）：星形胶质细胞通过线粒体 β-氧化消耗 LD 中储存的 FA。星形胶质细胞对神经元源性 FA 的代谢可保护神经元免受 FA 毒性。破坏这种与代谢 FA 的紧密协调耦合可能会导致增加 HIV 之间的应激协同作用期间报告的星形胶质细胞能量代谢和神经缺陷感染和可卡因使用。