The role of platinum-regulated lipid metabolism in tau-related dementia

铂调节的脂质代谢在 tau 相关痴呆中的作用

• 批准号: 10713249
• 负责人: Lingtao Jin
• 金额: $ 41.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713249
• 关键词: Affect; Alzheimer' s Disease; Astrocytes; Astrocytosis; Brain; Cancer Patient; Carboplatin; Cells; Chemotherapy-Oncologic Procedure; Cisplatin; Cognitive; Communication; Complex; Data; Dementia; Dendritic Cells; Development; Disease Progression; Exhibits; Fatty Acids; Functional disorder; Genes; Glutamine; Homeostasis; Immune; In Vitro; Infiltration; Inflammatory; Knowledge; Link; Lipids; Malignant Neoplasms; Mediating; Metabolism; Microglia; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Pathogenesis; Pathologic; Pathology; Phenotype; Platinum; Platinum Compounds; Play; Production; Proteins; Regulation; Role; Severities; Severity of illness; Signal Transduction; Structural defect; TREM2 gene; Tauopathies; Testing; Toxic effect; Tumor-Derived; anti-cancer; cancer cell; chemotherapy; exosome; genetic variant; genome wide association study; in vivo; in vivo Model; lipid metabolism; long chain fatty acid; neuroinflammation; neurotoxicity; non-genetic; prevent; programs; response; risk variant; tau Proteins; tau aggregation; tau mutation; therapeutically effective; tumor; tumor microenvironment; uptake

PROJECT SUMMARY Alzheimer's disease (AD) is characterized by widely distributed neurofibrillary tangles (NFTs), which plays an important role in AD pathogenesis. NFTs are composed of abnormal tau aggregates filling the neurons. Pathologic tau can activate the proinflammatory signaling in microglia and induce neuroinflammation, which forms a “vicious cycle” and significantly contributes to the disease progression and severity of AD. Moreover, activated microglia can subsequently cause a pronounced transformation of astrocytes called "reactive astrocytosis", leading to substantial neurotoxicity in AD. Increasing evidence demonstrate a critical role of aberrant microglial lipid metabolism in AD. Microglia exhibit a “lacy” phenotype featuring highly enriched lipid droplets, and lipid-laden microglia represent a dysfunctional and proinflammatory state. These observations all point to an important functional link between aberrant lipid metabolism, microglial dysfunction, and neuroinflammation. However, there are still significant knowledge gaps in understanding the complex network including both genetic variants and non-genetic insults that induces lipid-mediated microglial dysfunction. We previously uncovered that tumor-derived long-chain fatty acids critically contribute to lipid accumulation and consequently dysfunction of tumor-infiltrating dendritic cells. Our preliminary data also discovered that platinum agent (e.g. cisplatin and carboplatin), one of the most widely used chemotherapy agents for a variety of cancers, further exacerbates lipid accumulation and dysfunction of dendritic cells through reprograming of lipid metabolism in cancer cells. While studying how platinum treatment affects lipid metabolism in cancer cells as well as surrounding immune cells, we unexpectedly discovered that platinum also induces aberrant lipid accumulation in the brain, particularly in microglia. Importantly, this platinum-induced reprograming of lipid metabolism is associated with tau pathology in vivo. Therefore, the recently discovered neuron-microglia “lipid communication” may be impacted by platinum treatment, which may contribute to neuroinflammation, pathologic tau spreading and AD disease progression. We hypothesize that, platinum treatment, through reprograming lipid metabolism in neurons, promotes production of neuron-derived, fatty acids-enriched exosomes, which leads to lipid accumulation in surrounding microglia. This platinum-induced lipid accumulation consequently induces proinflammatory state of microglia and drives neuroinflammation, which further promotes pathological tau spreading and severity of AD. We will test our hypothesis through the following aims: Aim 1: To investigate the mechanism by which platinum drives microglial lipid accumulation. Aim 2: To elucidate how platinum-induced neuron/microglial lipid reprogramming promotes neuroinflammation and AD progression.

项目总结 阿尔茨海默病(AD)的特点是广泛分布的神经原纤维缠结(NFT)，它扮演着一种 在AD发病机制中起重要作用。NFTs由充满神经元的异常tau聚集体组成。 病理性tau可以激活小胶质细胞中的促炎信号，诱导神经炎症，从而 形成一种“恶性循环”，对疾病的进展和AD的严重程度有很大的影响。此外， 激活的小胶质细胞随后会引起星形胶质细胞的显著转化，称为“反应性” 星形细胞增多症“，导致AD的实质性神经毒性。越来越多的证据表明， 阿尔茨海默病患者小胶质细胞脂代谢异常。小胶质细胞表现为“花边”表型，具有高度浓缩的脂类。 液滴和富含脂质的小胶质细胞代表功能障碍和促炎状态。这些观察都是 指出脂代谢异常、小胶质细胞功能障碍和 神经炎。然而，在理解复杂网络方面仍有很大的知识差距 包括导致脂质介导的小胶质细胞功能障碍的遗传变异和非遗传侮辱。 我们之前发现，肿瘤衍生的长链脂肪酸对脂肪堆积起关键作用。 从而导致肿瘤浸润性树突状细胞功能障碍。我们的初步数据还发现， 铂剂(如顺铂和卡铂)，最广泛使用的多种化疗药物之一 在癌症中，通过脂类的重新编程进一步加剧脂类的积累和树突状细胞的功能障碍 癌细胞的新陈代谢。在研究铂治疗如何影响癌细胞脂代谢的同时， 以及周围的免疫细胞，我们出人意料地发现，铂也会诱导异常的脂质 在大脑中积聚，特别是在小胶质细胞中。重要的是，这种铂诱导的脂类重新编程 体内的新陈代谢与tau病理有关。因此，新近发现的神经元-小胶质细胞脂质 铂类药物治疗可能会影响“沟通”，这可能会导致神经炎症、病理 Tau的扩散和AD疾病的进展。我们假设，铂治疗，通过重新编程脂质 神经元中的新陈代谢，促进神经元衍生的富含脂肪酸的外切体的产生，从而导致 脂肪堆积在周围的小胶质细胞中。这种铂诱导的脂质堆积因此导致 小胶质细胞的促炎状态，并推动神经炎症，从而进一步促进病理tau AD的扩散和严重程度。我们将通过以下目标来验证我们的假设：目标1：调查 铂促进小胶质细胞脂质堆积的机制。目的2：阐明铂是如何引起 神经元/小胶质细胞脂质重编程促进神经炎症和AD进展。