Metabolite-initiated protein misfolding may trigger Alzheimer's disease

• DOI: 10.1073/pnas.0400924101
• Publication Date: 2004-03-20T01:13:08Z
• Authors: Qinghai Zhang; Evan T. Powers; Jorge Nieva; Mary E. Huff; Maria A. Dendle; Jan Bieschke; Charles G. Glabe; Albert Eschenmoser; Paul Wentworth; Richard A. Lerner; Jeffery W. Kelly
• Keywords: Amyloid (mycology); Amyloid disease

Anfinsen showed that a protein's fold is specified by its sequence. Although it clear why mutant proteins form amyloid, harder to rationalize wild-type protein adopts native conformation in most individuals, but misfolds minority of others, what should be common extracellular environment. This discrepancy suggests another event likely triggers misfolding sporadic amyloid disease. One possibility an abnormal metabolite, generated only some covalently modifies the or peptide and causes misfold, evidence for this sparse. Candidate metabolites are suggested recently appreciated links between Alzheimer's disease (AD) atherosclerosis, known chronic inflammatory metabolites, newly discovered generation ozone during inflammation. Here we report detection cholesterol ozonolysis products human brains. These related, lipid-derived aldehyde modify Aβ, dramatically accelerating amyloidogenesis vitro , providing possible chemical link hypercholesterolemia, inflammation, AD.