Identification of the target kinase in Aß-mediated cholesterol homeostasis

A 介导的胆固醇稳态中目标激酶的鉴定

• 批准号: 26723513
• 负责人: Professor Dr. Tobias Hartmann
• 金额: --
• 依托单位: Deutsches Institut für Demenzprävention (DIDP)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/26723513?language=en
• 关键词: Identification; target; kinase; mediated; cholesterol

Links between Alzheimer s disease (AD) and cholesterol were recently established. Amyloid-beta (Aß), a cleavage product of the Alzheimer Amyloid Precursor Protein, is assumed to be the causative factor in AD. Very recently, we identified a first physiological Aß function. Aß acts as a down-regulator of cholesterol de novo synthesis. The ultimate target enzyme for Aß in cholesterol synthesis is the HMG-Co A reductase (HMGR). Importantly, Aß generation is analog to sterol regulatory binding protein (SREBP) processing. Aß lowers, whereas SREBP processing increases cholesterol de novo synthesis, resulting in counteracting activities. A direct Aß-HMGR interaction is unlikely, because of their subcellular localization. In agreement with already published as well as preliminary data, it is likely that Aß acts, directly or indirectly, on 5-AMP activated protein kinase (AMPK), an enzyme which down regulates HMGR activity. Here we will investigate how the Aß signal is transmitted to cholesterol regulation. We will utilize AMPK and several functionally characterized and cholesterol-level modulating kinases. Moreover, it will be important to establish whether this regulation differs between brain and peripheral organs.

最近确定了阿尔茨海默病和S病(AD)和胆固醇之间的联系。淀粉样β蛋白是阿尔茨海默病前体蛋白的切割产物，被认为是阿尔茨海默病的致病因素。最近，我们发现了第一个生理学A？函数。A？作为胆固醇从头合成的下调因子。胆固醇合成的最终靶酶是HMG-CoA还原酶(HMGR)。重要的是，A？代类似于固醇调节结合蛋白(SREBP)的处理。A？降低，而SREBP处理增加胆固醇从头合成，导致抵消活性。由于A？-HMGR的亚细胞定位，直接的A？-HMGR相互作用不太可能。与已发表的和初步的数据一致，Aü很可能直接或间接地作用于5-AMP激活的蛋白激酶(AMPK)，这是一种下调HMGR活性的酶。在这里，我们将研究A？信号是如何传递到胆固醇调节的。我们将利用AMPK和几种具有功能特征和胆固醇水平的调节蛋白激酶。此外，重要的是要确定这种调节在大脑和外周器官之间是否有所不同。