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

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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.