NF-κB as a driver of neurotoxic astrocytes in Alzheimers disease

项目总结 星形胶质细胞在深受阿尔茨海默病(AD)影响的脑区参与多种内在功能。 在生理条件下，星形胶质细胞调节突触可塑性，提供营养和支持 神经元存活，并有助于更高的认知功能和免疫反应。然而，星形胶质细胞 在神经退行性疾病中失去保护性表型并变得越来越有害。 鉴于星形胶质细胞与大脑疾病的密切联系，令人惊讶的是，人们对星形胶质细胞 这些细胞在疾病过程中的病理功能。在AD中，星形胶质细胞变得越来越突出 疾病会继续发展。我们之前展示过，这些细胞是高度可塑性的，可以产生信号， 或加重或减轻AD的发病，表明调节星形细胞功能可能有 治疗价值。虽然机制研究还有待发展，但转录组和蛋白质组学 方法已经为潜在驱动致病特性的分子过程提供了线索 星形胶质细胞，其中核因子-κB(NF-κB)是很有前途的候选因子。核因子-κB是一种关键的转录因子 炎症调节因子，与许多慢性免疫相关疾病有关。我们的建议旨在 使用新的工程基因工具研究星形细胞NF-κB慢性激活的假说 损害大脑功能，并推动AD的发病。这些研究将提供关键的证据 核因子-κB在星形胶质细胞功能中的作用及其作为治疗AD靶点的潜力。 好了！

PROJECT SUMMARY Astrocytes participate in several intrinsic functions in brain areas deeply affected by Alzheimer's disease (AD). Under physiological conditions, astrocytes modulate synaptic plasticity, provide nutrients and support for neuronal survival, and contribute to higher cognitive functions and immune responses. However, astrocytes lose their protective phenotype and become increasingly detrimental during neurodegenerative disorders. Given the close association of astrocytes to brain disorders, it is surprising how little is known about the pathological function of these cells in disease processes. In AD, astrocytes become increasingly prominent as the disease progresses. We previously showed that these cells are highly plastic and can produce signals that either exacerbate or mitigate AD pathogenesis, indicating that modulating astrocytic function could have therapeutic value. Although mechanistic studies are yet to be developed, transcriptomic and proteomic approaches have provided clues to the molecular processes that potentially drive the pathogenic properties of astrocytes, with the nuclear factor-κB (NF-κB) being a promising candidate. NF-κB is a key transcriptional regulator of inflammation that has been linked to many chronic immune-related diseases. Our proposal seeks to use newly engineered genetic tools to investigate the hypothesis that chronic activation of astrocytic NF-κB impairs brain function and drives AD pathogenesis. These studies will provide definitive evidence of the pivotal role played by NF-κB in astrocytic function and its potential as a target to treat AD. !