Metabolite-initiated protein misfolding may trigger Alzheimer's disease.
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.
Zhang
Qinghai
Q
Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Powers
Evan T
ET
Nieva
Jorge
J
Huff
Mary E
ME
Dendle
Maria A
MA
Bieschke
Jan
J
Glabe
Charles G
CG
Eschenmoser
Albert
A
Wentworth
Paul
P
Lerner
Richard A
RA
Kelly
Jeffery W
JW
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
D016229:Amyloid beta-Peptides