Ozone unfolds Alzheimer's mysteries

The brain chemistry of cholesterol metabolites.

Alzheimer’s disease continues to hold many mysteries for researchers. For example, it is still not understood why a brain protein should adopt a native conformation in some individuals but misfold in others. Now an international team of researchers claims to have discovered that the proteins may misfold because of a curious link to cholesterol.

Many research teams have linked the misfolding of secreted amyloid beta peptide residues (A?) to Alzheimer’s disease. When A? misfolds it first forms spherical assemblies then fibrillar quaternary amyloid structures.

Alzheimer’s disease shares risk factors with atherosclerosis, a hardening of the arteries. Recent research has suggested that one of these risk factors, inflammation, can generate ozone, which reacts with cholesterol to generate a series of metabolites.

A team of researchers, led by Jeffery Kelly at The Scripps Research Institute in La Jolla, California, speculated that aldehyde groups in these metabolites could covalently modify A? in the brain by condensing with amines present in the peptides.The researchers detected the cholesterol ozonolysis products in human brain samples, four of which came from Alzheimer’s patients. In vitro tests then showed that incubating two of the compounds, a ketoaldehyde and its aldol product, with A? caused spherical assemblies to form. In further tests, the team discovered that these formed the fibrillar aggregates characteristic of Alzheimer’s disease.

Kelly told Chemistry World that he would be interested in developing drugs that reduce or prevent the formation of the cholesterol ozonolysis products. The Lerner Research Institute, Cleveland, Ohio, US, is working on the mechanisms by which ozone forms, and Kelly predicts that he will need this information. The team has yet to start developing any drugs, but ’will in the near future’, he revealed.

Emma Davies