AD results from aggregates of a misfolded form of amyloid β peptide (Aβ). Misfolding occasionally results from processing flaws or mutations in the Aβ precursor, but most patients have normal Aβ. Zhang et al. show that even normal Aβ folds abnormally when cholesterol by-products modify it.
Cholesterol itself did not affect Aβ, but cholesterol modified by reactive oxygen species (which are produced during inflammation) to generate an aldehyde group reacted with Aβ and made it more hydrophobic. This altered form aggregates at much lower concentrations than does normal Aβ–concentrations that are found in the brain.
Although brain samples did not show higher levels of the cholesterol aldehydes in AD patients, only small amounts of these metabolites are needed to jump start aggregation. “The creation of compounds that are reactive could be from an event occurring years before an individual presents with AD,” says Kelly. So, as boxers already know, one good knock on the head might do more lasting damage than just a fleeting headache. ▪