Astrocyte-secreted chaperones as a non-cell autonomous form of neuronal protection in Alzheimer's disease

目前，全球有超过4600万人和英国有85万人患有痴呆症和阿尔茨海默病，预计这一数字每20年将翻一番。尽管许多人努力寻找这种疾病的新的疾病修饰疗法，但最近的临床试验未能显示出显着的益处，目前患者仅用缓解疾病症状的药物治疗。传统上，药物发现策略集中在神经元作为阿尔茨海默氏症和其他脑部疾病的主要靶点。在大脑中，神经元负责处理信息，学习和记忆，而其他专门的脑细胞称为神经胶质细胞是维持神经元健康和帮助神经元功能所必需的。为了能够设计有效的阿尔茨海默病治疗策略，我们不仅需要研究神经元如何变得功能失调，而且还需要更好地了解神经胶质细胞对神经元变性和疾病进展的贡献。该项目的目的是研究星形胶质细胞，最丰富的胶质细胞类型，如何保护阿尔茨海默病中的神经元。如果我们能够确定哪些是星形胶质细胞释放的介导神经保护的因子，我们将能够设计有效的治疗工具。这项研究计划将在莫里斯沃尔临床神经科学研究所进行，这是伦敦国王学院新建的高度跨学科的神经科学中心。我们已经建立了互补的合作，这将使我们能够采用一些阿尔茨海默病模型，包括小鼠神经元和神经胶质细胞培养物，小鼠脑切片和来自患者诱导多能干细胞的人类神经元。使用这些模型，我们将研究星形胶质细胞释放的影响大脑中异常蛋白质积累的因素，并确定这些因素如何保护阿尔茨海默病神经元免于死亡。我们的研究结果将提供临床前证据，以支持后续的治疗研究。这一建议将探讨增加星形胶质细胞释放的因子作为一种潜在的治疗策略，以防止阿尔茨海默病的神经元功能丧失的潜在好处。这是一种新的研究途径，可能会对我们对神经退行性机制的理解产生重大影响，并可能发现治疗阿尔茨海默病的新方法。

Currently, more than 46 million people worldwide and 850,000 people in the UK are living with dementia and Alzheimer's disease, a number that is expected to double every 20 years. Despite many efforts to find new disease-modifying therapies for this disease, recent clinical trials have failed to show significant benefits and currently patients are only treated with drugs that alleviate disease symptoms. Traditionally, drug discovery strategies have focused on neurons as the main targets in Alzheimer's and other brain disorders. In the brain, neurons are responsible for processing information, learning and memory, while other specialized brain cells called glial cells are necessary to maintain neuron health and to aid neuron function. To be able to design effective therapeutic strategies for Alzheimer's disease, we need to investigate not only how neurons become dysfunctional but also to better understand what is the contribution of glial cells to the degeneration of neurons and the disease progression. The aim of this project is to investigate how astrocytes, the most abundant type of glial cell, can protect neurons in Alzheimer's disease. If we are able to identify which are the factors released from astrocytes that mediate neuroprotection, we will be able to design effective therapeutic tools.This research program will be carried out at the Maurice Wohl Clinical Neuroscience Institute, a newly built highly interdisciplinary neuroscience center at King's College London. We have established complementary collaborations that will enable us to employ a number of models of Alzheimer's disease, including mouse neuron and glia cell cultures, mouse brain slices and human neurons derived from induced pluripotent stem cells from patients. Using these models, we will investigate what are the factors released from astrocytes that affect the accumulation of abnormal proteins in brain and we will determine how these factors can protect Alzheimer's disease neurons from dying. Our findings will provide pre-clinical evidence to support follow up therapeutic studies.This proposal will explore the potential benefits of increasing astrocyte-released factors as a potential therapeutic strategy to prevent loss of neuron function in Alzheimer's disease. This is a novel avenue of research, which could have a significant impact on our understanding of neurodegenerative mechanisms and that may identify new ways to treat Alzheimer's disease.