A link between lipid-mediated signaling and inflammation during neurodegeneration

神经变性过程中脂质介导的信号传导与炎症之间的联系

• 批准号: 10701487
• 负责人: Mariana Atina Pehar
• 金额: $ 53.44万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701487
• 关键词: APP-PS1; Abeta clearance; Affect; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Anti-Inflammatory Agents; Appearance; Arachidonic Acids; Astrocytes; Biological Markers; Biology; Brain Diseases; Cell Culture Techniques; Cell physiology; Cellular Metabolic Process; Central Nervous System; Cerebrospinal Fluid; Clinical; Cognitive; Cytoplasmic Granules; Data; Defect; Dementia; Development; Disease Progression; Docosahexaenoic Acids; Down-Regulation; Elderly; Endoplasmic Reticulum; Energy-Generating Resources; Fatty Acids; Functional disorder; Gene Expression; Genetic Transcription; Gliosis; Goals; Growth; Human; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Intracellular Transport; Ligands; Link; Lipids; Longitudinal Studies; Mediating; Memory; Metabolic; Metabolism; Mitochondria; Molecular; Monitor; Mus; Nerve Degeneration; Neurites; Neurofibrillary Tangles; Outcome Measure; Oxidative Stress; PPAR gamma; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Persons; Phenotype; Positron-Emission Tomography; Process; Production; Proteomics; Receptor Signaling; Regulation; Research; Resolution; Risk; Role; Sampling; Senile Plaques; Signal Transduction; Signaling Molecule; Symptoms; System; Testing; Therapeutic; Thinking; Treatment Efficacy; Up-Regulation; Wisconsin; adeno-associated viral vector; aged; association cortex; behavior test; cyclooxygenase 2; cytokine; enzyme substrate; extracellular; fatty acid metabolism; fatty acid-binding proteins; gene therapy; human subject; immunoregulation; in vivo; induced pluripotent stem cell; inflammatory marker; innovation; lipid metabolism; lipid transport; metabolomics; mitochondrial dysfunction; mouse model; neuroinflammation; neuron loss; neurotoxicity; novel; novel marker; postnatal; preclinical study; response; skills; tau aggregation; therapeutic target; transcription factor; transcriptomics; translational study; uptake

Abstract Neuroinflammation, oxidative stress, and mitochondrial dysfunction have been associated with the pathophysiology of Alzheimer’s disease (AD), either as a primary cause or as a secondary component of the pathogenic process. AD, the most common cause of dementia in the elderly, is characterized by the accumulation of intracellular tau neurofibrillary tangles and extracellular amyloid plaques. The main component of the plaque core is the amyloid β (Aβ)-peptide. Longitudinal studies have shown that the appearance of plaques and tangles, together with markers of inflammation, starts decades before the onset of clinical symptoms. Some components of the inflammatory response may promote resolution and facilitate Aβ clearance, while sustained inflammation induces neurotoxicity. Fatty acid-binding proteins (FABPs) have recently emerged as key regulators of cell metabolism and inflammation. They control the intracellular transport of lipids that function as both, ligands for transcription factors and substrates for enzymes involved in lipid metabolism. In AD and other pathological conditions, astrocytes upregulate FABP7 expression. This increase in FABP7 expression has been linked to mitochondrial dysfunction. Accordingly, FABP7 is especially abundant in astrocytes that are rich in cytoplasmic granules originated from degraded mitochondria. Our preliminary data indicate that FABP7 participates in the development of a pro-inflammatory phenotype in human astrocytes, while down-regulation of FABP7 reduces the expression of inflammatory markers. FABP7 regulates the inflammatory response at least through 2 different mechanisms that have been independently pursued as therapeutic targets in AD. These include the regulation of peroxisome proliferator-activated receptor (PPAR) signaling and the regulation of arachidonic acid metabolism by cyclooxygenase-2 (COX-2). This suggests that FABP7 could function as a key regulator of the inflammatory response in astrocytes and constitutes a potential therapeutic target in AD. By simultaneously regulating two central components of the inflammatory response, targeting FABP7 may confer enhanced therapeutic efficacy over conventional anti-inflammatory therapies. On the aforementioned context, we will determine the mechanism by which FABP7 regulates the inflammatory response in astrocytes (Aim 1) and we will determine the therapeutic potential of targeting FABP7 in AD mouse models (Aim 2). Lastly in Aim 3 we will evaluate the extent to which FABP7 expression correlates with biomarkers of AD pathology and the rate of cognitive decline in human subjects. This proposal will contribute to the understanding of the role of FABP7 in neurodegeneration and will provide in vivo proof of the value of modulating FABP7 expression as a therapeutic target in AD.

抽象的 神经炎症，氧化应激和线粒体功能障碍与 阿尔茨海默氏病（AD）的病理生理，无论是作为主要原因还是作为次要成分 致病过程。 AD是痴呆症中最常见的原因，其特征是 细胞内TAU神经原纤维缠结和细胞外淀粉样斑块的积累。主组件 斑块核是淀粉样β（Aβ）肽。纵向研究表明斑块的出现 缠结以及创新标记，在临床症状发作之前数十年开始。一些 炎症反应的组成部分可能会促进分辨率并促进Aβ清除率，同时持续 炎症诱导神经毒性。脂肪酸结合蛋白（FABP）最近已成为钥匙 细胞代谢和炎症的调节剂。他们控制脂质的细胞内转运 两者都是转录因子和底物的配体参与脂质代谢的酶。在广告和其他 病理条件，星形胶质细胞上调FABP7表达。 Fabp7表达的这种增加已经 与线粒体功能障碍有关。据认为，FabP7在丰富的星形胶质细胞中特别丰富 细胞质颗粒起源于降解的线粒体。我们的初步数据表明Fabp7 参与人类星形胶质细胞中促炎表型的发展，而下调 FABP7降低了炎症标记的表达。 FABP7至少调节炎症反应 通过2种不同的机制，这些机制已独立追求为AD的治疗靶标。这些 包括调节过氧化物体增殖物激活受体（PPAR）信号传导和调节 环氧酶-2（COX-2）的花生四烯酸代谢。这表明FabP7可以用作钥匙 星形胶质细胞中炎症反应的调节剂，构成了AD中潜在的治疗靶点。经过 简单地控制炎症反应的两个主要组成部分，针对FabP7 5月会议 对常规抗炎疗法的治疗效率提高。在优先考虑的上下文中 我们将确定FABP7调节星形胶质细胞炎症反应的机制（AIM 1） 我们将确定在AD小鼠模型中靶向FABP7的治疗潜力（AIM 2）。最后在AIM 3 我们将评估FABP7表达与AD病理的生物标志物和速率相关的程度 人类受试者的认知能力下降。该建议将有助于理解FabP7的作用 在神经变性中，将提供体内证明调节FabP7表达作为治疗的价值 AD中的目标。