Identification of the target kinase in Aß-mediated cholesterol homeostasis

阿尔茨海默病（AD）和胆固醇之间的联系最近被确定。淀粉样蛋白-β（A β）是阿尔茨海默氏淀粉样蛋白前体蛋白的裂解产物，被认为是AD的致病因素。最近，我们发现了第一个生理性的Aparthotopic功能。阿托伐他汀作为胆固醇从头合成的下调剂。在胆固醇合成中，腺苷酸的最终靶酶是HMG-CoA还原酶（HMGR）。重要的是，ARAP 4的产生类似于固醇调节结合蛋白（SREBP）的加工。胆固醇降低，而SREBP加工增加胆固醇从头合成，导致抵消活动。由于它们的亚细胞定位，ARAM-HMGR不太可能直接相互作用。与已经发表的以及初步的数据一致，很可能是，ARAPINE直接或间接地作用于5-AMP活化的蛋白激酶（AMPK），一种下调HMGR活性的酶。在这里，我们将研究如何Ablation信号传递到胆固醇调节。我们将利用AMPK和几种功能特征和胆固醇水平调节激酶。此外，重要的是要确定这种调节是否在大脑和外周器官之间存在差异。

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.