Acetylation of Aβ40 Alters Aggregation in the Presence and Absence of Lipid Membranes

A hallmark of Alzheimer's disease (AD) is the formation of senile plaques comprised of the beta-amyloid (A beta) peptide. A beta fibrillization is a complex nucleation-dependent process involving a variety of metastable intermediate aggregates and features the formation of inter- and intramolecular salt bridges involving lysine residues, K16 and K28. Cationic lysine residues also mediate protein-lipid interactions via association with anionic lipid headgroups. As several toxic mechanisms attributed to A beta involve membrane interactions, the impact of acetylation on A beta(40) aggregation in the presence and absence of membranes was determined. Using chemical acetylation, varying mixtures of acetylated and nonacetylated A beta(40) were produced. With increasing acetylation, fibril and oligomer formation decreased, eventually completely arresting fibrillization. In the presence of total brain lipid extract (TBLE) vesicles, acetylation reduced the interaction of A beta(40) with membranes; however, fibrils still formed at near complete levels of acetylation. Additionally, the combination of TBLE and acetylated A beta promoted annular aggregates. Finally, toxicity associated with A beta(40) was reduced with increasing acetylation in a cell culture assay. These results suggest that in the absence of membranes that the cationic character of lysine plays a major role in fibril formation. However, acetylation promotes unique aggregation pathways in the presence of lipid membranes.