The Role of Chromogranin A in Tauopathy

项目概要 包括阿尔茨海默病 (AD) 和额颞叶痴呆 (FTD) 在内的 Tau蛋白病影响着三分之一的人 世界人口超过 65 岁。为了应对这场健康危机，工业和学术实验室已经 一直在尝试开发药物。这些努力已经进行了数百项临床试验，但取得的成功 仅限于减缓少数疾病的进展。这一失败表明我们缺乏对这些问题如何运作的了解。 疾病引发。因此，需要更好地了解早期的生化过程 这些疾病。多种因素带来的监管失衡可能导致这些疾病的发生 高度异质性。为了解决这些复杂的问题，找出导致这些问题的新因素至关重要 tau蛋白病的发展。 该提案将确定分泌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，合成并储存在内分泌激素储存颗粒中 细胞和神经元充当神经递质的调节器。它对维持组织起着重要作用 体内平衡、炎症和胰岛素敏感性。据报道，CSF 中 CgA 浓度较高 AD 患者中经常观察到 Aβ 斑块被激活的小胶质细胞包围并刺激 细胞毒素的释放。然而，这些先前的报告是基于体外培养实验 细胞，但在了解 CgA 在 AD 体内的作用方面尚未取得真正的进展。此外，无论CgA 在 tau 发病机制中发挥的作用尚完全未知。 三个在 tau 蛋白病、CgA 生理学和炎症方面拥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 PS19 的认知、神经炎症和代谢 转基因小鼠。我们收集的初步信息表明 i) PS19 小鼠具有胰岛素抵抗性； ii) CgA 在 PS19 中过度表达，iii) PS19 小鼠大脑中炎症通路被激活。我们的数据 结合已发表的报告，我们推测 CgA 的过度表达导致 i) 代谢 压力，ii) 神经炎症和 iii) 神经递质失衡。这些异常现象密切相关 与导致全面疾病的病理性 tau 蛋白积累增加有关。来测试我们的 假设，我们将生成 PS19/Chga-/- 和 PS19/Chga-/ 小鼠，并确定 CgA 是否耗尽 通过比较 i) 病理性 tau 积累和传播，ii) 改善神经退行性变 神经炎症，iii）认知功能，以及 iv）代谢表型和寿命，这些与年龄有关 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.