The butter flavorant, diacetyl, exacerbates β-amyloid cytotoxicity.
Diacetyl (DA), an ubiquitous butter-flavoring agent, was found to influence several aspects of amyloid-β (Aβ) aggregation--one of the two primary pathologies associated with Alzheimer's disease. Thioflavin T fluorescence and circular dichroism spectroscopic measurements revealed that DA accelerates Aβ¹⁻⁴² aggregation into soluble and ultimately insoluble β-pleated sheet structures. DA was found to covalently bind to Arg⁵ of Aβ¹⁻⁴² through proteolytic digestion-mass spectrometric experiments. These biophysical and chemical effects translated into the potentiation of Aβ¹⁻⁴² cytotoxicity by DA toward SH-SY5Y cells in culture. DA easily traversed through a MDR1-MDCK cell monolayer, an in vitro model of the blood-brain barrier. Additionally, DA was found not only to be resistant to but also inhibitory toward glyoxalase I, the primary initiator of detoxification of amyloid-promoting reactive dicarbonyl species that are generated naturally in large amounts by neuronal tissue. In light of the chronic exposure of industry workers to DA, this study raises the troubling possibility of long-term neurological toxicity mediated by DA.
Center for Drug Design, Academic Health Center, University of Minnesota , 308 Harvard Street SE, 8-123A WDH, Minneapolis, Minnesota 55455, USA.
Swati S
SS
More
Ashish P
AP
Vartak
Robert
R
Vince
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D052160:Benzothiazoles; D001812:Blood-Brain Barrier / Q000378:metabolism; D002079:Butter / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival; D002942:Circular Dichroism; D003931:Diacetyl / Q000378:metabolism / Q000633:toxicity*; D004285:Dogs; D005421:Flavoring Agents / Q000378:metabolism / Q000633:toxicity*; D005456:Fluorescent Dyes / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D010539:Permeability; D011487:Protein Conformation / Q000187:drug effects; D013844:Thiazoles / Q000032:analysis / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005421:Flavoring Agents; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C009462:thioflavin T; D002079:Butter; D007791:Lactoylglutathione Lyase; D003931:Diacetyl