JPND LOss of neurotrophic factors in neurodegenerative DEmentias: Back to the crossroads of proteins (LODE)

神经退行性疾病，如阿尔茨海默病和帕金森病在我们的社会中非常常见，但它们是如何发展的，我们能做些什么来治疗它们尚不清楚。事实上，这些疾病是无法治愈的。已知的是，这些疾病中的一些蛋白质会形成异常的聚集体，这与神经元细胞的死亡和神经元整合网络的破坏有关，导致记忆丧失（如阿尔茨海默病）或运动问题（如帕金森病）。外泌体是细胞间携带分子的小囊泡，在维持神经元之间的通信中非常重要，特别是当它们的网络中断时。我们认为，外泌体无法形成和携带这些分子导致神经元的丧失和疾病。神经元由外泌体携带的生长因子支持，而外泌体的产生又依赖于这些生长因子，但外泌体与生长因子之间的相互关系尚不清楚。这项应用的目的是澄清这种关系，并利用我们的发现来提供保护和支持神经元的生长因子。为了实现这些目标，我们将检查外泌体中这些生长因子的存在，看看是否可以通过使用纳米颗粒将生长因子输送到患病个体的人类神经元中来克服这种缺陷，转基因疾病小鼠模型，并测试患有这种疾病的患者是否存在这种缺陷。这些结果将有助于揭示神经退行性变的新机制，除了新的干预目标外，还可能揭示新的疾病标志物。

Neurodegenerative diseases such as Alzheimer's and Parkinson's disease are very common in our society but how they develop and what we can do to treat them is not yet clear. Indeed no cure for these diseases is available. What is known is that some proteins in these diseases form abnormal aggregates that are associated with the death of the neuronal cells and disruption of the network in which neurons are integrated, leading to memory loss (like in Alzheimer's disease) or movement problems (like in Parkinson's disease). Exosomes are small vesicles that carry molecules between cells, and are very important in maintaining communication between neurons, especially when their networks are interrupted. We propose that ,the failure of exosomes to form and carry these molecules contributes to loss of neurons and disease. Neurons are supported by growth factors which are carried by exosomes, while exosome production in turn can depend on these growth factors but the mutual relationship between exosomes and growth factors is not well understood. The aim of this application is to clarify this relationship and exploit our findings to deliver growth factors that protect and support the neurons. To achieve these aims, we will examine the presence of these growth factors in exosomes and see if the deficiency can be overcome by delivering the growth factors using nanoparticles to human neurons from diseased individuals, transgenic mouse models of disease and test if the deficiency in patients with the disease. The results will help to shed light on new mechanisms contributing to neurodegeneration and may also unmask novel disease markers besides new targets for intervention.