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 β-amyloid (Aβ) peptide. Aβ 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 Aβ involve membrane interactions, the impact of acetylation on Aβ40 aggregation in the presence and absence of membranes was determined. Using chemical acetylation, varying mixtures of acetylated and non-acetylated Aβ40 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 Aβ40 with membranes; however, fibrils still formed at near complete lev...