ABSTRACT
SCOPE: Epidemiological studies have shown that coffee consumption may be associated with a lower risk of developing several neurological disorders, including Alzheimer's disease (AD). Caffeine is a prominent candidate component underlying the preventive effects of coffee; however, the contribution of other constituents is unclear. To clarify this issue, the effect of roasting coffee beans on ß-secretase (BACE1) expression in human neuroblastoma SH-SY5Y cells is investigated. METHODS AND RESULTS: Coffee (2%) reduces Aß accumulation in culture medium to 80% of control levels after 24 h. Accordingly, BACE1 expression is decreased to 70% of control levels at 12 h. Experiments using cycloheximide and MG132, a proteasome inhibitor, reveal that coffee enhanced BACE1 degradation through activation of proteasomal activity. Furthermore, coffee activates cAMP-dependent protein kinase, and consequently, phosphorylation of a serine residue of proteasome 26S subunit, non-ATPase 11 (PSMD11). Pyrocatechol, a strong antioxidant known as catechol or 1,2-dihydroxybenzene, produced from chlorogenic acid during roasting, also reduces BACE1 expression by activation of proteasomal activity. Furthermore, pyrocatechol reduces Aß production in SH-SY5Y cells. CONCLUSION: The data suggest that the roasting process may be crucial for the protective effects of coffee consumption in AD.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/metabolism , Coffee , Alzheimer Disease/metabolism , Alzheimer Disease/prevention & control , Amyloid Precursor Protein Secretases/genetics , Aspartic Acid Endopeptidases/genetics , Catechols/pharmacology , Cell Line, Tumor , Coffee/chemistry , Cyclic AMP-Dependent Protein Kinases/metabolism , Food Handling , Humans , Neuroblastoma/metabolism , Plant Extracts/analysis , Proteasome Endopeptidase Complex/metabolism , Proteolysis/drug effectsABSTRACT
Cataracts are a major cause of blindness worldwide. As anticataract pharmaceutical therapies require longterm treatment, identifying anticataract compounds that are ubiquitous in the human diet, have no adverse effects and are affordable, is of paramount importance. The present study focused on hesperetin and its derived compounds, hesperetin stearic acid ester (HesS) and hesperetin oleic acid ester (HesO), in order to investigate their therapeutic potential to treat cataracts in a selenite animal model. Thirteendayold Sprague Dawley rats were divided into 12 groups. Animals in groups 1 and 7 were subcutaneously injected with vehicle, those in groups 2 and 8 were administered hesperetin, those in groups 3 and 9 received stearic acid, those in groups 4 and 10 were injected with oleic acid, those in groups 5 and 11 were administered HesS, and those in groups 6 and 12 received HesO (10 nmol/kg body weight on days 0, 1 and 2). Animals in groups 7 to 12 were treated with sodium selenite (20 µmol/kg body weight given 4 h following the test compound treatment on day 0) to induce cataract. On day 6, rats had less severe central opacities and lower stage cataracts than rats in the selenite treatmentonly control groups. The levels of glutathione (GSH) and ascorbic acid (AsA) in lenses with seleniteinduced cataracts declined to onethird of that of controls, and the reduction in GSH and AsA levels was rescued following hesperetin, HesS or HesO treatment, with concentrations remaining to 7080% of that of controls. However, there were no changes in the plasma levels of GSH and AsA following treatments. Administration of either hesperetin or hesperetinderived compounds prevented the reduction of chaperone activity in the lens, and rats treated with HesS or HesO treatment had significantly greater chaperone activity than hesperetintreated rats. Collectively, these results suggested that hesperetin and hesperetinderived compounds may be novel drug compounds that have the potential to prevent or delay the onset of cataracts.