Acetylation of Aβ 40 Alters Aggregation in the Presence and Absence of Lipid Membranes
Year: 2019
Type: article
Abstract: 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 Aβ 40 aggregation in the presence and absence of membranes was determined. Using chemical acetylation, varying mixtures of acetylated and nonacetylated Aβ 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 Aβ 40 with membranes; however, fibrils still formed at near complete levels of acetylation. Additionally, the combination of TBLE and acetylated Aβ promoted annular aggregates. Finally, toxicity associated with Aβ 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.
Source: ACS Chemical Neuroscience
Institution: West Virginia University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2994838049