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，但它们如何发展以及我们可以做些什么来治疗它们还不清楚。事实上，这些疾病没有治愈方法。已知的是，这些疾病中的一些蛋白质形成异常聚集体，这些异常聚集体与神经元细胞的死亡和神经元整合的网络的破坏有关，导致记忆丧失（如阿尔茨海默病）或运动问题（如帕金森病）。外泌体是在细胞之间携带分子的小囊泡，在维持神经元之间的通信方面非常重要，特别是当它们的网络中断时。我们认为，外泌体未能形成和携带这些分子导致神经元和疾病的损失。神经元由外泌体携带的生长因子支持，而外泌体的产生反过来可以依赖于这些生长因子，但外泌体和生长因子之间的相互关系还没有很好地理解。本申请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，我们将检查这些生长因子在外泌体中的存在，看看是否可以通过使用纳米颗粒将生长因子递送到来自患病个体的人类神经元，转基因小鼠疾病模型来克服这种缺陷，并测试疾病患者是否存在缺陷。这些结果将有助于揭示导致神经退行性变的新机制，也可能揭示除了新的干预靶点之外的新疾病标志物。

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.