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

项目摘要 阿尔茨海默病（AD）的特征是广泛分布的神经元缠结（NFT），其在阿尔茨海默病的发病中起重要作用。 在AD发病机制中的重要作用。NFT由填充神经元的异常tau聚集体组成。 病理性tau蛋白可以激活小胶质细胞中的促炎信号并诱导神经炎症， 形成“恶性循环”，并显著促进AD的疾病进展和严重程度。此外，委员会认为， 活化的小胶质细胞随后可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中的大量神经毒性。越来越多的证据表明， AD中异常的小胶质细胞脂质代谢。小胶质细胞表现出“花边”表型，其特征在于高度富集脂质 液滴和脂质负载的小胶质细胞代表功能障碍和促炎状态。所有这些观察 指出异常脂质代谢，小胶质细胞功能障碍， 神经炎症然而，在理解复杂网络方面仍然存在重大的知识差距 包括遗传变异和诱导脂质介导的小胶质细胞功能障碍的非遗传损伤。 我们以前发现，肿瘤源性长链脂肪酸对脂质积累有重要作用 并因此导致肿瘤浸润树突细胞的功能障碍。我们的初步数据还发现， 铂剂（例如顺铂和卡铂），是用于多种化疗的最广泛使用的化疗剂之一。 进一步加剧脂质积聚和树突状细胞功能障碍，通过脂质重编程， 癌细胞的代谢。在研究铂治疗如何影响癌细胞的脂质代谢时， 以及周围的免疫细胞，我们意外地发现，铂也诱导异常脂质 在大脑中积累，特别是在小胶质细胞中。重要的是，这种铂诱导的脂质重编程 代谢与体内tau病理学相关。因此，最近发现的神经元-小胶质细胞“脂质 “沟通”可能受到铂治疗的影响，这可能导致神经炎症、病理性 tau扩散和AD疾病进展。我们假设，铂治疗，通过重新编程脂质， 神经元中的代谢，促进神经元衍生的富含脂肪酸的外泌体的产生，这导致 周围小胶质细胞中的脂质积聚。这种铂诱导的脂质积聚因此诱导 小胶质细胞的促炎状态并驱动神经炎症，这进一步促进病理性tau蛋白 AD的传播和严重程度。我们将通过以下目的来检验我们的假设：目的1：调查 铂驱动小胶质细胞脂质积聚的机制。目的2：阐明铂诱导 神经元/小胶质细胞脂质重编程促进神经炎症和AD进展。

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.