Dose-Dependent Inhibition of BACE-1 by the Monoterpenoid 2,3,4,4-Tetramethyl-5-methylenecyclopent-2-enone in Cellular and Mouse Models of Alzheimer鈥檚 Disease

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• 作者：Rita Videira ; Pedro Castanheira ; M谩rio Gr茫os ; Rosa Resende ; L铆gia Salgueiro ; Carlos Faro ; Carlos Cavaleiro
• 刊名：Journal of Natural Products
• 出版年：2014
• 出版时间：June 27, 2014
• 年：2014
• 卷：77
• 期：6
• 页码：1275-1279
• 全文大小：260K
• ISSN：1520-6025

文摘

BACE-1 is an aspartic protease involved in the conversion of amyloid precursor protein (APP) to amyloid-尾 (A尾) in vivo, which is one of the key steps in the development and progression of Alzheimer鈥檚 disease. In a previous screening procedure for inhibitors of BACE-1 activity, the oil of Lavandula luisieri was identified as the most potent among several essential oils. The inhibitory effect of this essential oil on A尾 production was also demonstrated in a cellular assay. The composition of the volatile oil and the isolation of the compound responsible for the inhibitory activity were also reported. The present work focused on the characterization of the inhibition of BACE-1 by this active compound, a monoterpene necrodane ketone, 2,3,4,4-tetramethyl-5-methylenecyclopent-2-enone (<b>1b>), with assessment of its Kb>ib> value and the type of inhibition. The dose-related effects of the compound were also evaluated using two different cell lines, with determinations of the respective ECb>50b> values. The entire oil and the 2,3,4,4-tetramethyl-5-methylenecyclopent-2-enone (<b>1b>) were tested on a triple transgenic mouse model of Alzheimer鈥檚 disease. The overall results showed that compound <b>1b> displayed a dose-dependent inhibition of BACE-1 in cellular and mouse models of Alzheimer鈥檚 disease and is therefore capable of passing through cellular membranes and the blood鈥揵rain barrier.