Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation
Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation
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DOI：
10.1096/fj.10-167361
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发表时间：
2011-01-01
期刊：
影响因子：
4.8
通讯作者：
Marambaud, Philippe
中科院分区：
文献类型：
--
作者：
Vingtdeux, Valerie;Chandakkar, Pallavi;Marambaud, Philippe
AMP活化蛋白激酶（AMPK）是一种代谢传感器，通过控制自噬和蛋白质降解等多种稳态机制参与细胞内能量代谢。最近，我们报道了白藜芦醇激活AMPK促进淀粉样β（A β）肽的自噬依赖性降解，淀粉样β（A β）肽是阿尔茨海默病大脑老年斑的核心成分。为了鉴定更有效的A β降解增强剂，我们筛选了一个合成小分子文库，这些小分子是根据它们与白藜芦醇的结构相似性而选择的。在这里，我们报告了一系列结构相关分子的鉴定，RSVA系列，其抑制细胞系中A β积累的作用比白藜芦醇强近40倍。这些分子中的两种，RSVA 314和RSVA 405，被进一步表征，并发现促进AMPK的CaMKK β依赖性活化，抑制mTOR（雷帕霉素的哺乳动物靶），并促进自噬以增加溶酶体系统的A β降解（表观EC 50类似于1 μ M）。这项工作将RSVA化合物鉴定为有希望的先导分子，用于开发一类新的AMPK激活药物，控制mTOR信号传导，自噬和A β清除。Vingtdeux，V.，P.，赵，H.，d'Abramo，C.，戴维斯，P.，Marambaud，P.新型AMPK合成小分子活化剂作为自噬和淀粉样β肽降解的增强剂。FASEB J.25，219-231（2011）. www.fasebj.org
AMP-activated protein kinase (AMPK) is a metabolic sensor involved in intracellular energy metabolism through the control of several homeostatic mechanisms, which include autophagy and protein degradation. Recently, we reported that AMPK activation by resveratrol promotes autophagy-dependent degradation of the amyloid-beta (A beta) peptides, the core components of the cerebral senile plaques in Alzheimer's disease. To identify more potent enhancers of A beta degradation, we screened a library of synthetic small molecules selected for their structural similarities with resveratrol. Here, we report the identification of a series of structurally related molecules, the RSVA series, which inhibited A beta accumulation in cell lines nearly 40 times more potently than did resveratrol. Two of these molecules, RSVA314 and RSVA405, were further characterized and were found to facilitate CaMKK beta-dependent activation of AMPK, to inhibit mTOR (mammalian target of rapamycin), and to promote autophagy to increase A beta degradation by the lysosomal system (apparent EC50 similar to 1 mu M). This work identifies the RSVA compounds as promising lead molecules for the development of a new class of AMPK activating drugs controlling mTOR signaling, autophagy, and A beta clearance.-Vingtdeux, V., Chandakkar, P., Zhao, H., d'Abramo, C., Davies, P., Marambaud, P. Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation. FASEB J. 25, 219-231 (2011). www.fasebj.org