title: 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's disease.
abstract: BACE-1 is an aspartic protease involved in the conversion of amyloid precursor protein (APP) to amyloid-β (Aβ) in vivo, which is one of the key steps in the development and progression of Alzheimer's 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 Aβ 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 (1), with assessment of its Ki 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 EC50 values. The entire oil and the 2,3,4,4-tetramethyl-5-methylenecyclopent-2-enone (1) were tested on a triple transgenic mouse model of Alzheimer's disease. The overall results showed that compound 1 displayed a dose-dependent inhibition of BACE-1 in cellular and mouse models of Alzheimer's disease and is therefore capable of passing through cellular membranes and the blood-brain barrier.
authors.affiliation: Center of Pharmaceutical Studies, Faculty of Pharmacy, University of Coimbra , Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Videira
authors.forename: Pedro
authors.initials: P
authors.lastname: Castanheira
authors.forename: Mário
authors.initials: M
authors.lastname: Grãos
authors.forename: Rosa
authors.initials: R
authors.lastname: Resende
authors.forename: Lígia
authors.initials: L
authors.lastname: Salgueiro
authors.forename: Carlos
authors.initials: C
authors.lastname: Faro
authors.forename: Carlos
authors.initials: C
authors.lastname: Cavaleiro
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D027523:Lavandula / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010938:Plant Oils / Q000737:chemistry
chemical_list: C000590847:2,3,4,4-tetramethyl-5-methylenecyclopent-2-enone; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D039821:Monoterpenes; D010938:Plant Oils; D057055:Aspartic Acid Proteases; D002402:Cathepsin D