Identification of the target kinase in Aß-mediated cholesterol homeostasis

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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.