The Role of Chromogranin A in Tauopathy

项目摘要 包括阿尔茨海默病（AD）和额颞叶痴呆（FTD）在内的Tau病影响了三分之一的老年人， 65岁以上的世界人口。为了科普这一健康危机，工业和学术实验室已经 一直在尝试开发药物。这些努力已经导致了数百项临床试验，但成功 仅限于减缓疾病的发展。失败表明我们缺乏知识， 疾病爆发了。因此，需要更好地了解早期阶段的生物化学过程 这些疾病。有可能是监管失衡带来的诸多因素使这些疾病 高度异质性。为了解决这些复杂的问题，关键是要确定新的因素， tau蛋白病的发展。 这项提议将确定分泌性蛋白因子嗜铬粒蛋白A（CgA）是否在 tau蛋白病CgA是一种酸性糖蛋白，由内分泌系统的激素储存颗粒合成和储存。 作为神经递质调节器的细胞和神经元。它在维持组织中起着重要作用 稳态、炎症和胰岛素敏感性。据报道，CgA浓度在以下患者的CSF中较高： 在AD患者中，经常观察到Aβ斑块周围有活化的小胶质细胞和刺激物 释放细胞毒素然而，这些先前的报告是基于培养的细胞中的体外实验。 细胞中，并没有真实的进展已经取得了了解CgA的作用，在体内AD。此外，无论CGA 在tau发病机制中起作用是完全未知的。 三个在tau蛋白病，CgA生理学和炎症方面具有专业知识的研究小组将开展工作 共同研究CgA是否以及如何影响认知、神经炎症和PS19代谢 转基因小鼠我们已经收集了初步的信息，表明i）PS19小鼠是胰岛素抵抗的; ii）CgA在PS19中过表达，和iii）炎症途径在PS19小鼠脑中被激活。我们的数据 沿着已发表的报告使我们假设CgA的过表达负责i）代谢性疾病， 压力，ii）神经炎症和iii）神经递质失衡。这些异常与 与病理性tau积累增加相关，导致全面疾病。来测试我们 假设，我们将产生PS19/Chga-/-和PS19/Chga-/+小鼠，并确定CgA的消耗是否与PS19/Chga-/+小鼠的CgA消耗有关。 通过比较i）病理性tau积累和增殖，ii） 神经炎症，iii）认知功能，和iv）代谢表型和寿命，在这些和年龄- 匹配的PS19/Chga+/+（PS19）和非转基因/Chga+/+（野生型）小鼠。

Project Summary Tauopathies including Alzheimer's Disease (AD) and frontotemporal dementia (FTD) affect a third of the world population aged over 65. To cope with this health crisis, industrial and academic laboratories have been trying to develop drugs. These efforts have resulted in hundreds of clinical trials, but the success has been limited to only slowing the disease by a handful. The failure points our lack of knowledge of how these diseases set off. Therefore, there is a need to better understand the biochemical processes in the early stage of these diseases. It is possible that regulatory imbalances brought by many factors rendering these diseases highly heterogeneous. To address these complex issues, it is critical to identify new factors contributing to the development of tauopathies. This proposal will determine if a secretory protein factor, chromogranin A (CgA), plays any role in tauopathies. CgA is an acidic glycoprotein synthesized and stored in hormone storage granules of endocrine cells and neurons acting as a regulator of neurotransmitter. It plays an important role in maintaining tissue homeostasis, inflammation, and insulin sensitivity. CgA concentration was reported to be high in the CSF of AD patients and was frequently observed in Aβ plaques surrounded by activated microglia and stimulates the release of cytotoxins. These previous reports, however, are based on in vitro experiments in cultured cells and no real progress has been made to understand CgA's role in AD in vivo. Moreover, whether CgA plays a role in tau pathogenesis is completely unknown. Three research groups with expertise in tauopathy, CgA physiology, and inflammation will work together to investigate if and how CgA affects cognition, neuroinflammation, and metabolism of PS19 transgenic mice. We have gathered preliminary information showing that i) PS19 mice are insulin-resistant; ii) CgA is overexpressed in PS19 and iii) an inflammatory pathway is activated in PS19 mice brain. Our data along with published reports led us to hypothesize that overexpression of CgA is responsible for i) metabolic stress, ii) neuroinflammation and iii) neurotransmitter imbalance. These abnormalities are intimately associated with heightened pathological tau accumulation resulting in the full-blown disease. To test our hypothesis, we will generate PS19/Chga-/- and PS19/Chga-/+ mice, and determine if the depletion of CgA ameliorates neurodegeneration by comparing i) pathological tau accumulation and propagation, ii) neuroinflammation, iii) cognitive function, and iv) metabolic phenotype and longevity, in these and age- matched PS19/Chga+/+ (PS19) and non-transgenic/Chga+/+ (wild type) mice.