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.

摘要 神经炎症、氧化应激和线粒体功能障碍与脑缺血相关。 阿尔茨海默病（AD）的病理生理学，无论是作为主要原因或作为次要组成部分， 致病过程AD是老年痴呆症的最常见原因，其特征在于 细胞内tau神经元缠结和细胞外淀粉样斑块的积累。主要成分 是淀粉样β（Aβ）肽。纵向研究表明，斑块的出现 和缠结，以及炎症的标志物，在临床症状出现之前几十年就开始了。一些 炎症反应的组分可能促进消退并促进Aβ清除， 炎症诱导神经毒性。脂肪酸结合蛋白（FABPs）最近成为了 调节细胞代谢和炎症。它们控制脂质的细胞内转运， 转录因子的配体和参与脂质代谢的酶的底物。在AD和其他 在病理条件下，星形胶质细胞上调FABP 7表达。FABP 7表达的这种增加已经被证实。 与线粒体功能障碍有关因此，FABP 7在富含FABP 7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，FABP 7 参与人星形胶质细胞中促炎表型的形成，而下调 FABP 7减少炎症标志物的表达。FABP 7至少调节炎症反应， 通过2种不同的机制，已被独立追求作为治疗AD的目标。这些 包括过氧化物酶体增殖物激活受体（PPAR）信号传导的调节和 花生四烯酸通过环氧合酶-2（考克斯-2）代谢。这表明FABP 7可以作为一种关键， 星形胶质细胞中的炎症反应的调节剂，并构成AD的潜在治疗靶点。通过 同时调节炎症反应的两个中心组分，靶向FABP 7可以赋予 相对于常规抗炎疗法的增强的治疗功效。在上述背景下， 我们将确定FABP 7调节星形胶质细胞炎症反应的机制（目标1） 并且我们将确定在AD小鼠模型中靶向FABP 7的治疗潜力（目的2）。在Aim 3中 我们将评估FABP 7表达与AD病理学生物标志物相关的程度， 认知能力的下降。这一建议将有助于理解FABP 7的作用 并将提供调节FABP 7表达作为治疗神经变性的价值的体内证据。 目标在AD