S100A9 induces aggregation-prone conformation in Abeta peptides: a combined experimental and simulation study

Abstract

Inflammation is one of the prominent pathological features in Alzheimer's disease (AD). Recently, there have been various proposed roles of neuroinflammation, such as the driving forces, bystander, byproduct or the neuroprotective response. Notwithstanding these diverse possible mechanisms, experiments have found that S100A9 is one of the pro-inflammatory proteins abundant and over-expressed in the inflammation sites of AD. In this paper, we examine the role of S100A9 in the oligomerization process of Aβ peptides by means of replica exchange molecular dynamics simulation and experimental investigations. Our experiments, based on atomic force microscopy and Thioflavin T spectroscopic assays, have clearly indicated that the close interaction between S100A9 and Aβ has significantly enhanced the Aβ oligomerization. In line with the experimental observation, our simulation studies have revealed that the pro-inflammatory S100A9 protein interacts with the Aβ peptides directly, mainly through hydrophobic interactions with the Aβ central hydrophobic core region. In addition, the formation of hydrogen bonds between the residues of the S100A9 homodimer and the two ends of the Aβ peptides is found to cause a straightening of the Aβ_12–24 peptides. A more straight Aβ_12–24 peptide with a higher β-content then may function as a template to induce the folding of new incoming Aβ peptides, which leads to the formation of aggregation-prone oligomers.