Aggregation of beta-amyloid peptide is promoted by membrane phospholipid metabolites elevated in Alzheimer's disease brain.

Abstract

Increased amounts of beta-amyloid (A beta) peptide deposits are found in Alzheimer's disease brain. These amyloid deposits have been implicated in the pathophysiology of this common dementing illness. A beta peptides have been shown to be toxic to neurons in cell culture, and this toxicity is critically dependent on the aggregation of the peptide into cross-beta-pleated sheet fibrils. Also, in vivo and postmortem NMR studies have shown changes in certain brain membrane phospholipid metabolites in normal aging and more extensive alterations in patients with Alzheimer's disease. The finding that membrane phospholipids affect the aggregation of A beta suggests that the abnormalities in membrane metabolism found in Alzheimer's disease could affect the deposition of A beta in vivo. Therefore, we examined the effect of membrane phospholipid metabolites that are altered in Alzheimer's disease brain on the aggregation of A beta(1-40) using a light scattering method. Certain metabolites (glycerophosphocholine, glycerophosphoethanolamine, and alpha-glycerophosphate) augment the aggregation of A beta. Other membrane phospholipid metabolites (phosphocholine, phosphoethanolamine, and inositol-1-phosphate) have no effect. We conclude that increased membrane phospholipid metabolite concentrations may play a role in the deposition of A beta seen in normal aging and the even greater deposition of A beta observed in Alzheimer's disease.