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 阿尔茨海默病 (AD) 的病理生理学，无论是作为主要原因还是作为次要因素 AD 是老年人痴呆的最常见原因，其特点是 细胞内tau神经原纤维缠结和细胞外淀粉样斑块堆积的主要成分。 斑块的核心是β淀粉样蛋白(Aβ)-肽，纵向研究表明斑块的出现。 缠结以及炎症标志物在临床症状出现前几十年就开始了。 炎症反应的成分可能会促进消退并促进 Aβ 清除，同时持续 炎症诱发神经毒性最近已成为关键。 它们控制细胞内脂质的转运，起到细胞代谢和炎症的调节作用。 两者都是转录因子的配体和参与脂质代谢的酶的底物。 病理条件下，星形胶质细胞上调 FABP7 表达，FABP7 表达增加。 因此，FABP7 在富含 FABP7 的星形胶质细胞中尤其丰富。 我们的初步数据表明 FABP7 源自降解的线粒体。 参与人星形胶质细胞促炎表型的发展，同时下调 FABP7 减少炎症标志物的表达 FABP7 至少调节炎症反应。 通过两种不同的机制，这两种机制已被独立地作为 AD 的治疗靶标。 包括过氧化物酶体增殖物激活受体 (PPAR) 信号传导的调节和 环加氧酶-2 (COX-2) 的花生四烯酸代谢这表明 FABP7 可能发挥关键作用。 星形胶质细胞炎症反应的调节剂，是 AD 的潜在治疗靶点。 同时调节炎症反应的两个核心成分，靶向 FABP7 可能会赋予 在上述情况下，与传统抗炎治疗相比，疗效增强。 我们将确定 FABP7 调节星形胶质细胞炎症反应的机制（目标 1） 我们将确定针对 AD 小鼠模型的 FABP7 的治疗潜力（目标 2）。 我们将评估 FABP7 表达与 AD 病理学生物标志物的相关程度以及相关率 该提议将有助于理解 FABP7 的作用。 神经退行性疾病中的研究，并将提供调节 FABP7 表达作为治疗价值的体内证据 公元后的目标