title: Metabolite-initiated protein misfolding may trigger Alzheimer's disease.
abstract: Anfinsen showed that a protein's fold is specified by its sequence. Although it is clear why mutant proteins form amyloid, it is harder to rationalize why a wild-type protein adopts a native conformation in most individuals, but it misfolds in a minority of others, in what should be a common extracellular environment. This discrepancy suggests that another event likely triggers misfolding in sporadic amyloid disease. One possibility is that an abnormal metabolite, generated only in some individuals, covalently modifies the protein or peptide and causes it to misfold, but evidence for this is sparse. Candidate metabolites are suggested by the recently appreciated links between Alzheimer's disease (AD) and atherosclerosis, known chronic inflammatory metabolites, and the newly discovered generation of ozone during inflammation. Here we report detection of cholesterol ozonolysis products in human brains. These products and a related, lipid-derived aldehyde covalently modify Abeta, dramatically accelerating its amyloidogenesis in vitro, providing a possible chemical link between hypercholesterolemia, inflammation, atherosclerosis, and sporadic AD.
authors.affiliation: Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Zhang
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.forename: Jorge
authors.initials: J
authors.lastname: Nieva
authors.forename: Mary E
authors.initials: ME
authors.lastname: Huff
authors.forename: Maria A
authors.initials: MA
authors.lastname: Dendle
authors.forename: Jan
authors.initials: J
authors.lastname: Bieschke
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
authors.forename: Albert
authors.initials: A
authors.lastname: Eschenmoser
authors.forename: Paul
authors.initials: P
authors.lastname: Wentworth
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lerner
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D018625:Microscopy, Atomic Force; D017510:Protein Folding
chemical_list: D016229:Amyloid beta-Peptides